The complex morphological, anatomical, physiological, and chemical mechanisms within the aging brain have been the hot topic of research for centuries. The aging process alters the brain structure that affects functions and cognitions, but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease. Beyond these observable, mild morphological shifts, significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain. Understanding these changes is important for maintaining cognitive health, especially given the increasing prevalence of age-related conditions that affect cognition. This review aims to explore the age-induced changes in brain plasticity and molecular processes, differentiating normal aging from the pathogenesis of Alzheimer's disease, thereby providing insights into predicting the risk of dementia, particularly Alzheimer's disease.

Berbamine (BBM), a natural bisbenzylisoquinoline alkaloid, has demonstrated promising effects in ameliorating pathological process and inflammation response in central neuronal system (CNS). Alzheimer's disease (AD), primarily characterized by amyloid-beta (Aβ)-containing extra-cellular plaques and abnormal "autophagy-brake regulation" of neuroinflammation, currently lacks of effective therapeutic options. Therapeutics of BBM on AD is indeed intriguing, and the potential targets and mechanisms are vague yet.

This study is designed to elucidate the therapeutic potential of BBM on AD, focusing particularly on its ability to enhance autophagy, induce microglial M2 polarization, and to uncover the underlying molecular mechanisms and implicated targets.

The therapeutic efficacy of BBM was systematically investigated in APP/PS1 mice, with a focus on its potential to enhance autophagy, induce M2 polarization in microglia, and facilitate the clearance of Aβ plaques. Cognitive function was rigorously assessed through a series of behavioral tests, including the Morris Water Maze and Object Location Task. Immunofluorescence was employed to visualize the spatial distribution of inflammatory cytokines and autophagic markers within the brain parenchyma. Quantitative measurements of these cytokines were obtained using enzyme-linked immunosorbent assay (ELISA). Western blotting was utilized to analyze protein profiles associated with autophagy and microglial phenotypes. Additionally, chemo-proteomics and molecular docking techniques were applied to identify the key molecular targets of BBM.

BBM treatment significantly ameliorated cognitive dysfunction and reduced Aβ plaque deposition in APP/PS1 transgenic mice. Notably, BBM promoted microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, accompanied by attenuation of neuroinflammation. Mechanistically, BBM exerted its effects through inhibition of mTOR signaling via direct interaction with the FKBP12-rapamycin-binding domain, thereby restoring autophagic flux and facilitating M2 microglial polarization. The mTOR activator MHY1485 abrogated the beneficial effects of BBM, highlighting the pivotal role of mTOR inhibition in its mechanism of action.

BBM promotes M2 microglial polarization and restores autophagic flux in AD by inhibiting mTOR signaling, representing a novel dual-modulatory mechanism for AD intervention. These findings highlight BBM's ability to target mTOR and intersecting pathways, offering a promising disease-modifying therapeutic approach for AD and other neurodegenerative disorders.

The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation of beta-amyloid and phosphorylated tau, synaptic damage, and mitochondrial abnormalities in the brain, leading to the progressive loss of cognitive function and memory. In AD, emerging research suggests that lifestyle factors such as a healthy diet and regular exercise may play a significant role in delaying the onset and progression of the disease. Mitochondria are often referred to as the powerhouse of the cell, as they are responsible for producing the energy to cells, including neurons to maintain cognitive function. Our article elaborates on how mitochondrial quality and function decline with age and AD, leading to an increase in oxidative stress and a decrease in ATP production. Decline in mitochondrial quality can impair cellular functions contributing to the development and progression of disease with the loss of neuronal functions in AD. This article also covered mitophagy, the process by which damaged or dysfunctional mitochondria are selectively removed from the cell to maintain cellular homeostasis. Impaired mitophagy has been implicated in the progression and pathogenesis of AD. We also discussed the impact of impaired mitophagy implicated in AD, as the accumulation of damaged mitochondria can lead to increased oxidative stress. We expounded how dietary interventions and exercise can help to improve mitochondrial quality, and mitochondrial function and enhance mitophagy in AD. A diet rich in antioxidants, polyphenols, and mitochondria-targeted small molecules has been shown to enhance mitochondrial function and protect against oxidative stress, particularly in neurons with aged and mild cognitively impaired subjects and AD patients. Promoting a healthy lifestyle, mainly balanced diet and regular exercise that support mitochondrial health, in an individual can potentially delay the onset and progression of AD. In conclusion, a healthy diet and regular exercise play a crucial role in maintaining mitochondrial quality and mitochondrial function, in turn, enhancing mitophagy and synaptic activities that delay AD in the elderly populations.

Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.

Alzheimer's disease (AD) is the most common and severe degenerative disorder of the central nervous system in the elderly, profoundly impacting patients' quality of life. However, effective therapeutic agents for AD are still lacking. Bazi Bushen capsule (BZBS) is a traditional Chinese herbal compound with potential neuroprotective effects, yet its underlying mechanisms remain poorly understood.

In this study, we utilized APP/PS1 transgenic mice to assess the therapeutic efficacy of BZBS. Initially, we evaluated the spatial learning and memory of the mice using the Barnes maze. The brain microcirculation was assessed through a small-animal ultrasound system, two-photon in vivo imaging, and micro-computed tomography angiography. Molecular, biochemical, and pathological analyses were conducted on brain tissues. Through network pharmacology, we identified potential intervention pathways and targets for BZBS in the treatment of AD, which we subsequently validated both in vivo and in vitro. Additionally, we employed molecular virtual docking screening and biolayer interferometry to elucidate the direct interactions of ginsenoside Rg5 and ginsenoside Ro in BZBS with AMPK and LKB1 proteins.

The BZBS intervention significantly enhanced spatial learning and memory in APP/PS1 mice while decreasing Aβ deposition. Furthermore, BZBS protected cerebrovascular homeostasis and mitigated neuroinflammation, as evidenced by decreased blood-brain barrier permeability, increased expression of tight-junction proteins, and restored cerebral blood flow. Mechanistically, ginsenosides Rg5 and Ro in BZBS directly bind to AMPK and LKB1 proteins, activating the LKB1-AMPK-SIRT1 signaling pathway, promoting autophagy and mitochondrial autophagy, and alleviating oxidative stress damage in endothelial cells.

BZBS enhances autophagy-related activity, decreases Aβ deposition, and improves endothelial cell homeostasis through the activation of the LKB1-AMPK-SIRT1 signaling pathway, ultimately leading to improved cognitive function in mice with AD. This study highlights the importance of enhancing autophagic activity and maintaining cerebrovascular homeostasis in mitigating cognitive decline in AD, providing evidence and new insights into the application of compound medicines for treating age-related neurological disorders.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, behavioral impairments, and psychiatric comorbidities. The pathogenesis of AD remains incompletely elucidated, despite advances in dominant hypotheses such as the β-amyloid (Aβ) cascade, tauopathy, cholinergic deficiency, and neuroinflammation mechanisms. However, these hypotheses inadequately explain the multifactorial nature of AD, which exposes limitations in our understanding of its mechanisms. Mitochondrial dysfunction is known to play a pivotal role in AD, and since patients exhibit intracellular mitochondrial dysfunction and structural changes in the brain at an early stage, correcting the imbalance of mitochondrial homeostasis and the cytopathological changes caused by it may be a potential target for early treatment of AD. Mitochondrial structural abnormalities accelerate AD pathogenesis. For instance, structural and functional alterations in the mitochondria-associated endoplasmic reticulum membrane (MAM) can disrupt intracellular Ca2⁺ homeostasis and cholesterol metabolism, consequently promoting Aβ accumulation. In addition, the overaccumulation of Aβ and hyperphosphorylated tau proteins can further damage neurons by disrupting mitochondrial integrity and mitophagy, thereby amplifying pathological aggregation and exacerbating neurodegeneration in AD. Furthermore, Aβ deposition and abnormal tau proteins can disrupt mitochondrial dynamics through dysregulation of fission/fusion proteins, leading to excessive mitochondrial fragmentation and subsequent dysfunction. Additionally, hyperphosphorylated tau proteins can impair mitochondrial transport, resulting in axonal dysfunction in AD. This article reviews the biological significance of mitochondrial structural morphology, dynamics, and mitochondrial DNA (mtDNA) instability in AD pathology, emphasizing mitophagy abnormalities as a critical contributor to AD progression. Additionally, mitochondrial biogenesis and proteostasis are critical for maintaining mitochondrial function and integrity. Impairments in these processes have been implicated in the progression of AD, further highlighting the multifaceted role of mitochondrial dysfunction in neurodegeneration. It further discusses the therapeutic potential of mitochondria-targeted strategies for AD drug development.

Diabetic encephalopathy (DE) is a neurological complication characterized by neuroinflammation, cognitive impairment, and memory decline, with its pathogenesis closely linked to the activation of the NLRP3 inflammasome. As a central regulator of the innate immune system, the NLRP3 inflammasome plays a pivotal role in DE progression by mediating neuroinflammation, pyroptosis, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, and microglial polarization. This review systematically explores the molecular mechanisms by which the NLRP3 inflammasome contributes to DE, focusing on its role in neuroinflammatory cascades and neuronal damage, as well as the diabetes-associated physiological changes that exacerbate DE pathogenesis. Furthermore, we summarize emerging therapeutic strategies targeting the NLRP3 inflammasome, including small-molecule inhibitors and bioactive compounds derived from traditional herbal medicine, highlighting their potential for DE treatment. These findings not only advance our understanding of DE but also provide a foundation for developing NLRP3-targeted pharmacological interventions.

Mitochondrial autophagy is a critical quality control mechanism that eliminates dysfunctional mitochondria to maintain cellular homeostasis. Among receptor-dependent mitophagy pathways, FUN14 domain-containing 1 (FUNDC1)-a mitochondrial outer membrane protein harboring an LC3-interacting region (LIR)-plays a central role by directly binding to LC3 under stress conditions, thereby initiating autophagosome encapsulation of damaged organelles. Emerging evidence implicates FUNDC1 dysregulation in neurodegenerative diseases, particularly Alzheimer's disease (AD), where defective mitophagy exacerbates hallmark pathologies including Aβ plaque deposition and hyperphosphorylated Tau-driven neurofibrillary tangles. Despite advances, the molecular interplay between FUNDC1 phosphorylation states (e.g., Ser13/Ser17/Tyr18) and AD progression remains poorly defined. This review systematically examines FUNDC1's dual regulatory role in mitophagy, its mechanistic links to Aβ and Tau pathologies, and the therapeutic potential of targeting FUNDC1-associated kinases (e.g., ULK1, CK2) or downstream effectors (e.g., DRP1, OPA1) to counteract mitochondrial dysfunction in AD. By synthesizing recent preclinical and clinical findings, we aim to bridge the gap between FUNDC1 biology and AD therapeutics, highlighting actionable nodes for drug development.

Viruses pose a significant challenge and threat to human health, as demonstrated by the current COVID-19 pandemic. Neurodegeneration, particularly in the case of Alzheimer's disease (AD), is significantly influenced by viral infections. AD is a neurodegenerative disease that affects people of all ages and poses a significant threat to millions of individuals worldwide. The precise mechanism behind its development is not yet fully understood; however, the emergence and advancement of AD can be hastened by various environmental factors, such as bacterial and viral infections. There has been a longstanding suspicion that the herpes simplex virus-1 (HSV-1) may have a role to play in the development or advancement of AD. Reactivation of HSV-1 could potentially lead to damage to neurons, either by direct means or indirectly by triggering inflammation. This article provides an overview of the connection between HSV-1 infections and immune cells (astrocytes, microglia, and oligodendrocytes) in the progression of AD. It summarizes recent scientific research on how HSV-1 affects neurons, which could potentially shed light on the clinical features and treatment options for AD. In addition, the paper has explored the impact of HSV-1 on neurons and its role in various aspects of AD, such as Aβ secretion, tau hyperphosphorylation, metabolic dysregulation, oxidative damage, apoptosis, and autophagy. It is believed that the immune response triggered by HSV-1 reactivation plays a role in the development of neurodegeneration in AD. Despite the lack of a cure for AD, researchers have made significant efforts to study the clinical and pathological aspects of the disease, identify biomarkers, and gain insight into its underlying causes. The goal is to achieve early diagnosis and develop treatments that can modify the progression of the disease. The current article discusses the most promising therapy for combating the viral impacts, which provides additional evidence for the frequent reactivations of latent HSV-1 in the AD brain. However, further research is still required to establish the molecular and cellular mechanisms underlying the development of AD through the reactivation of HSV-1. This could potentially lead to new insights in drug development aimed at preventing HSV-1 reactivation and the subsequent development and progression of AD.

The link between tooth loss and cognitive impairment has become increasingly significant. Recent findings suggest that mitochondrial alteration in hippocampal neurons may mediate this relationship.

This study aimed to explore the mediating role of mitochondria in the relationship between tooth loss and cognitive function in Wistar rats.

Male Wistar rats (n = 20, 12 weeks old) were randomly divided into tooth extraction (TE) and sham groups. The model was established through upper molar extraction and sham operation respectively. Cognitive evaluations were performed using Morris water maze (MWM) test 8 weeks after the model establishment. Hippocampal neuron morphology was observed. Mitochondrial function was evaluated by ATP level and mitochondrial membrane potential (MMP). Mitophagy assessment involved conducting immunohistochemical and immunofluorescent staining of PTEN-induced kinase 1 (PINK1), Parkin (E3 ubiquitin ligase), translocase of outer mitochondrial membrane 20 (TOMM20), and microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, mitophagy protein alterations were analyzed using western blotting.

Memory impairment in the TE group was obvious 8 weeks after model establishment. Substantial hippocampal mitochondrial dysfunction was observed in the TE group, evidenced by notably decreased ATP production, decreased MMP level, and abnormal mitochondrial morphology in the hippocampus. Diminished mitophagy was detected by immunofluorescent staining, and further confirmed by immunostaining and western blotting, indicating diminished mitophagy marker levels in PINK1 and Parkin, along with decreased LC3II/I ratios and elevated Sequestosome-1 (SQSTM1/P62) levels, highlighting hippocampal mitophagy deficiency following tooth loss.

Tooth loss leads to mitochondrial disturbance and inhibits PINK1/Parkin-mediated mitophagy in hippocampal neurons, inducing cognitive impairment.

This study reveals mitochondria may mediate the effect of tooth loss on cognitive function, offering a theoretical basis for the prevention of oral health-associated cognitive decline.

Atherosclerosis (AS), a chronic inflammatory disease, remains a leading contributor to cardiovascular morbidity and mortality. Recent studies highlight the critical role of the cGAS-STING pathway-a key innate immune signaling cascade-in driving AS progression. This pathway is activated by cytoplasmic DNA from damaged cells, thereby triggering inflammation and accelerating plaque formation. While risk factors such as aging, obesity, smoking, hypertension, and diabetes are known to exacerbate AS, emerging evidence suggests that these factors may also enhance cGAS-STING pathway, which amplifies inflammatory responses. Targeting this pathway offers a promising therapeutic strategy to reduce the burden of cardiovascular diseases (CVD). In this review, we summarize the mechanisms of the cGAS-STING pathway, explore its role in AS, and evaluate potential inhibitors as future therapeutic candidates. By integrating current knowledge, we aim to provide insights for developing novel treatments to mitigate AS and CVD burden.

Cisplatin, a widely used chemotherapeutic agent, is known to induce premature ovarian insufficiency (POI) and infertility in women of reproductive age. Among the contributing factors, cisplatin-induced apoptosis of ovarian granulosa cells is considered a primary driver of ovarian dysfunction; however, the underlying mechanisms remain incompletely understood. In this study, we investigated the cytotoxicity of cisplatin on the granulosa cell line KGN in vitro and explored the associated mechanisms. Our results demonstrate that cisplatin induces KGN cell apoptosis in a dose-dependent manner and impairs mitochondrial function, as evidenced by excessive ROS production, membrane potential collapse, and reduced ATP synthesis. Mitophagy, a key cellular self-protection mechanism that selectively removes damaged mitochondria, was activated following cisplatin treatment, mitigating its detrimental effects on KGN cells. Activation of mitophagy with urolithin A (UA) ameliorated cisplatin-induced mitochondrial dysfunction and apoptosis, whereas inhibition of mitophagy with cyclosporine A (CsA) exacerbated these effects. Furthermore, pretreatment with the clinical drug melatonin significantly enhanced mitophagy, effectively attenuating cisplatin-induced apoptosis in KGN cells. This study proposes a novel therapeutic strategy for patients undergoing tumor chemotherapy, aiming to preserve treatment efficacy while reducing the adverse effects of chemotherapeutic agents on ovarian function, thereby improving patients' quality of life.

Mitochondrial quality control is instrumental in regulating neuronal health and survival. The receptor-mediated clearance of damaged mitochondria by autophagy, known as mitophagy, plays a key role in controlling mitochondrial homeostasis. Mutations in genes that regulate mitophagy are causative for familial forms of neurological disorders including Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). PINK1/Parkin-dependent mitophagy is the best studied mitophagy pathway, while more recent work has brought to light additional mitochondrial quality control mechanisms that operate either in parallel to or independent of PINK1/Parkin mitophagy. Here, we discuss our current understanding of mitophagy mechanisms operating in neurons to govern mitochondrial homeostasis. We also summarize progress in our understanding of the links between mitophagic dysfunction and neurodegeneration, and highlight the potential for therapeutic interventions to maintain mitochondrial health and neuronal function.

Mitochondria are indispensable in cells and play crucial roles in maintaining cellular homeostasis, energy production, and regulating cell death. Mitochondrial dysfunction has various manifestations, causing different diseases by affecting the diverse functions of mitochondria in the body. Previous studies have mainly focused on mitochondrial-related diseases caused by nuclear gene mutations or mitochondrial gene mutations, or mitochondrial dysfunction resulting from epigenetic regulation, such as DNA and histone modification. In recent years, as a popular research area, m6A has been involved in a variety of important processes under physiological and pathological conditions. However, there are few summaries on how RNA methylation, especially m6A RNA methylation, affects mitochondrial function. Additionally, the role of m6A in pathology through influencing mitochondrial function may provide us with a new perspective on disease treatment. In this review, we summarize several manifestations of mitochondrial dysfunction and compile examples from recent years of how m6A affects mitochondrial function and its role in some diseases.

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.

Curcumin is a natural polyphenol extracted from plants that can interact with various molecular targets, including antioxidant, antibacterial, anticancer, and anti-aging activities. Due to its variety of pharmacological activities and large margin pf safety, curcumin has been used in the prevention and treatment of various diseases, such as Alzheimer's, heart, and rheumatic immune diseases. To develop curcumin eye drops that can be used as antioxidant and antibacterial agents after phacoemulsification, we have designed a nano-based drug delivery system to improve curcumin bioavailability and duration of action. We successfully prepared zeolitic imidazolate framework-8 (ZIF-8) coated with chitosan-liposome (Cur@ZIF-8/CS-Lip) for curcumin delivery. It can release curcumin for over 20 hin vitroand exhibits excellent biosafety, antioxidant, and antibacterial activities. Therefore, we hypothesized that Cur@ZIF-8/CS-Lip could reduce the incidence of oxidative stress and infection after cataract surgery.

Mitochondrial dysfunction is a hallmark of Alzheimer's disease, but the scope and severity of these specific deficits across forms of Alzheimer's disease are not well characterized. We designed a high-throughput longitudinal phenotypic assay to track mitochondrial dynamics and bioenergetics in glutamatergic induced pluripotent stem cell (iPSC)-derived human neurons possessing mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and the amyloid beta precursor protein (APP). Each gene set was composed of iPSC-derived neurons from an Alzheimer's disease patient in addition to two to three engineered mutations with appropriate isogenic and age-matched controls. These iPSC-derived neurons were imaged every other day, beginning at 10 days in vitro, to assess how mitochondrial length and content change over a 10 day time course using a mitochondrially targeted reporter. A second cytosolic reporter allowed for visualization of neurites. Bioenergetics assays, focusing on mitochondrial respiration and individual electron transport chain complexes, were also surveyed over this time course. Mutations in all three genes altered mitochondrial function measured by basal, ATP-linked and maximal oxygen consumption rates and by spare respiratory capacity, with PSEN1/PSEN2 alleles being more severe than APP mutations. Electron flow through Complexes I-IV was decreased in PSEN1/PSEN2 mutations but, in contrast, APP alleles had only modest impairments of complexes I and II. We measured aspects of mitochondrial dynamics, including fragmentation and neurite degeneration, both of which were dramatic in PSEN1/PSEN2 alleles, but essentially absent in APP alleles. The marked differences in mitochondrial pathology might occur from the distinct ways in which amyloids are processed into amyloid beta peptides and might be correlated with the disease severity.

The presence of hyperphosphorylated Tau proteins, which mislocalize and form neurofibrillary tangles, and the accumulation of amyloid-β plaques are hallmark features of Alzheimer's disease (AD). These toxic protein aggregates contribute to synaptic impairment and neuronal dysfunction, underscoring the need for strategies aimed at effectively clearing or reducing these aggregates in the treatment of AD. In recent years, proteolysis targeting chimera (PROTAC) technology has emerged as a promising approach for selectively degrading dysfunctional proteins rather than merely inhibiting their function. This approach holds great potential for developing more effective interventions that could slow AD progression and improve patient outcomes. In this review, we first examine the pathological mechanisms underlying AD, focusing on abnormal protein degradation and accumulation. We then explore the evolution of PROTAC technology, its mechanisms of action, and the current status of drug development. Finally, we discuss the latest findings regarding the application of PROTACs in AD therapy, highlighting the potential benefits and limitations of this technology. Although promising, further clinical research is necessary to fully assess the safety and efficacy of PROTAC-based therapies for AD treatment.

Chemofog is a serious sequela commonly manifested among cancer patients receiving doxorubicin (DOX) chemotherapy. Our goal was to explore the abrogative action of α-Bisabolol (BISA), a phytochemical sesquiterpene, against DOX-induced cognitive deficit. Rats were allocated into 5 groups: Group I: control; Group II received BISA orally (100 mg/kg/day for 4 weeks); Group III received DOX (2 mg/kg/week/i.p.) for 4 weeks; Groups IV and V were administered BISA orally at 50 and 100 mg/kg, respectively plus DOX, i. p. Results: 1) BISA attenuated DOX-induced chemofog as shown in memory-related behavioral tests. 2) BISA restored the hippocampal histological structure and redox homeostasis via diminishing MDA content and upregulating Nrf2 and HO-1 genes. 3) BISA mitigated DOX-induced neuroinflammation through reducing NF-kB, TNF-α, IL-6, IL-1β, and GFAP expressions. 4) BISA repressed the hippocampal apoptosis via downregulating Bax gene and upregulating Bcl-2 gene. 5) BISA enhanced the synaptic plasticity by activating the BDNF/TrKB signaling and increasing the levels of neurotransmitters that enhance memory, i.e., ACh, 5-HT, and DA. BISA at 100 mg/kg/day exerted a better neuroprotection than BISA at 50 mg/kg/day. Thus, BISA may protect cancer patients from cognitive disorders caused by DOX.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

This study aimed to investigate the impact of chronic cerebral hypoperfusion (CCH) on cognitive function, amyloid-β (Aβ) deposition, cellular autophagy, and mitochondrial dynamics in an Alzheimer's disease (AD) mouse model, and to evaluate the intervention effects of autophagy modulation on these outcomes. Utilizing the APP/PS1 mouse model combined with CCH, we assessed cognitive function, Aβ deposition, and the expression levels of relevant proteins through behavioral tests and immunohistochemical analysis. Our findings revealed pronounced cognitive deficits and increased Aβ deposition in the AD + CCH group mice, along with upregulation of mitochondrial fission proteins (Drp1, Fis1) and downregulation of mitochondrial fusion proteins (Opa1, Mfn1), indicating a shift towards mitochondrial fission and promoting cell apoptosis. Additionally, alterations were observed in the expression levels of cellular autophagy-related proteins (LC3-II, P62), which were reversed by treatment with autophagic inhibitor 3-methyladenine (3-MA). Furthermore, the expression of mitochondrial autophagy-related proteins PINK1 and Parkin was affected, with 3-MA alleviating this effect. In summary, our study elucidates the complex interplay among cognitive decline, increased Aβ deposition, and mitochondrial dysfunction in the AD + CCH model, and suggests that modulating autophagy could be a potential therapeutic strategy for treating the AD + CCH model.

Alzheimer's disease (AD) involves complex alterations in biological pathways, making comprehensive blood biomarkers crucial for accurate and earlier diagnosis. However, the cost-effectiveness and operational complexity of method using blood-based biomarkers significantly limit its availability in clinical practice.

We developed low-cost, convenient machine learning-based with digital biomarkers (MLDB) using plasma spectra data to detect AD or mild cognitive impairment (MCI) from healthy controls (HCs) and discriminate AD from different types of neurodegenerative diseases. Retrospective data were gathered for 1324 individuals, including 293 with amyloid beta positive AD, 151 with mild cognitive impairment (MCI), 106 with Lewy body dementia (DLB), 106 with frontotemporal dementia (FTD), 135 with progressive supranuclear palsy (PSP) and 533 healthy controls (HCs) between July 2017 and August 2023.

Random forest classifier and feature selection procedures were used to select digital biomarkers. MLDB achieved area under the curves (AUCs) of 0.92 (AD vs. HC, Sensitivity 88.2%, specificity 84.1%), 0.89 (MCI vs. HC, Sensitivity 88.8%, specificity 86.4%), 0.83 (AD vs. DLB, Sensitivity 77.2%, specificity 74.6%), 0.80 (AD vs. FTD, sensitivity 74.2%, specificity 72.4%), and 0.93 (AD vs. PSP, sensitivity 76.1%, specificity 75.7%). Digital biomarkers distinguishing AD from HC were negatively correlated with plasma p-tau217 (r = -0.22, p < 0.05) and glial fibrillary acidic protein (GFAP) (r = -0.09, p < 0.05).

The ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) plasma spectra features can identify AD-related pathological changes. These spectral features serve as digital biomarkers, providing valuable support in the early screening and diagnosis of AD.

The National Natural Science Foundation of China, STI2030-Major Projects, National Key R&D Program of China, Outstanding Youth Fund of Hunan Provincial Natural Science Foundation, Hunan Health Commission Grant, Science and Technology Major Project of Hunan Province, Hunan Innovative Province Construction Project, Grant of National Clinical Research Center for Geriatric Disorders, Xiangya Hospital and Postdoctoral Fellowship Program of CPSF.

Mitophagy is a process by which cells selectively eliminate damaged or dysfunctional mitochondria through the autophagy-lysosome pathway, thereby maintaining mitochondrial quality and cellular homeostasis. This process is closely linked to the onset and progression of various heart diseases. Modern pharmacological research has demonstrated that phytochemicals can regulate mitochondrial homeostasis in cardiomyocytes through multiple mechanisms, influencing mitophagy and protecting cardiomyocytes, which in turn exerts anti-cardiovascular effects. However, the underlying mechanisms of these effects are not yet fully understood. This study summarizes the pharmacological effects and molecular mechanisms of mitophagy in heart diseases, aiming to provide reference for the research and treatment of phytochemicals targeting mitophagy against heart diseases. The results indicated that phytochemicals (such as Berberine, Ginsenoside Rg1, Quercetin, Resveratrol, Baicalein, and so on) can exert preventive and therapeutic effects on heart diseases (such as cardiac toxicity or damage, myocardial ischemia/reperfusion injury, heart failure, heart aging, cardiac hypertrophy, cardiomyopathy, and so on.) via regulating the PINK1/Parkin and FUNDC1-dependent mitophagy pathway. These compounds mainly exert their effects by regulating mitochondrial homeostasis, mitochondrial dynamics, mitochondrial oxidative stress, mitochondrial apoptosis, and mitochondrial energy metabolism. This study provides a reference that phytochemicals have effect on anti-cardiovascular effects by regulating mitophagy. However, further in-depth mechanistic and clinical research are needed in the future.

Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca2+ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca2+ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca2+ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca2+ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.

Inflammation is a pivotal characteristic of neurodegenerative diseases. The triggering receptor expressed on the myeloid cells 2 (TREM2) gene has previously been shown to suppress inflammation by directly inhibiting inflammation-related pathways. Mitochondrial dysfunction has recently emerged as another critical pathological manifestation of neurodegenerative diseases. Although TREM2 is involved in the regulation of cellular energy metabolism and mitochondrial autophagy, its role in the relationship between inflammation and mitochondrial autophagy remains unclear.

In this study, we generated TREM2-overexpressing BV-2 cells and established a neuroinflammatory model with LPS. We compared these cells with wild-type cells in terms of inflammation, metabolism, autophagy, and mitochondria using methods such as RT-qPCR, Western blotting, immunocytochemistry, transmission electron microscopy, and flow cytometry.

Microglia overexpressing TREM2 exhibited increased resistance to inflammation. Additionally, these cells inhibited the metabolic reprogramming that occurs early in LPS-induced inflammation, reduced ROS release, mitigated mitochondrial damage, maintained a certain level of autophagic activity, and cleared damaged mitochondria. Consequently, they alleviated the inflammation caused by the mitochondrial barrier.

ur results suggest that TREM2 can alleviate inflammation by maintaining cellular metabolic homeostasis and mitochondrial autophagy activity.

To investigate the effects of Nrf2 agonist tertiary butylhydroquinone (TBHQ)-stimulated neural stem cells (NSCs) transplantation (NSC(TBHQ)) on neuronal damage and cognitive deficits in an AD model and its underlying principles.

BHQ-treated NSCs were examined with or without Aβ1-42 to investigate the effects of TBHQ on the proliferation and differentiation functions. The mitophagy inhibitor Cyclosporine A (CSA) was used to explore the regulation of mitophagy by TBHQ. The no-, ethanol-, and TBHQ-treated NSCs were transplanted into the bilateral hippocampal region of model mice to explore the effects of NSC(TBHQ) on neuronal, cognitive, and mitochondrial functional impairments in mice.

TBHQ reversed the Aβ1-42-caused inhibition on NSC proliferation and differentiation, as well as on levels of mitochondrial membrane potential, adenosine triphosphate (ATP), and mitochondrial fusion-associated proteins. TBHQ alleviated the Aβ1-42-induced increase in apoptosis, mitochondrial damage, mitochondria-derived reactive oxygen species (mtROS), and mitochondrial fission-related proteins. TBHQ activated the Parkin, Beclin, LC3II/I, and COXIV expression, while inhibiting the p62 expression. CSA reversed the effects of TBHQ on NSC proliferation and differentiation. After NSC(TBHQ) transplantation, it not only further extended the dwell time in the target quadrant and shorten the time and distance for finding the hidden platform, but also further decreased the Aβ and p-Tau/Tau levels, while increasing the expression of NeuN. The effects of NSC(TBHQ) transplantation on mitochondrial function were consistent with the in vitro experiments.

The study shows that NSC(TBHQ) intensifies the beneficial impact of NSCs transplantation on cognitive impairment and neuronal damage in AD models, likely due to TBHQ's role in promoting NSCs growth and differentiation via mitophagy, thus laying a theoretical foundation for improving NSCs transplantation for AD.

Microglia serve as vital innate immune cells in the central nervous system, playing crucial roles in the generation and development of brain neurons, as well as mediating a series of immune and inflammatory responses. The morphologic transitions of microglia are closely linked to their function. With the advent of single-cell sequencing technology, the diversity of microglial subtypes is increasingly recognized. The intricate interactions between microglia and neuronal networks have significant implications for psychiatric disorders and neurodegenerative diseases. A deeper investigation of microglia in neurologic diseases such as Alzheimer disease, depression, and epilepsy can provide valuable insights in understanding the pathogenesis of diseases and exploring novel therapeutic strategies, thereby addressing issues related to central nervous system disorders.

Previous study has demonstrated lancao decoction (LC), a traditional Chinese medicine (TCM) fomula and recorded in "Huangdineijing", has a therapeutic effect on cognitive impairment (early clinical manifestations of alzheimer's disease (AD), which suggests that LC may have potential therapeutic advantages for AD. Whether LC has the therapeutic effect on AD and its potential mechanisms were still further indicated.

In this study, we aimed to uncover the potential advantage and neuronal mechanisms of LC in the treatment of AD in APP/PS1 mice in the hippocampus.

We chose APP/PS1 mice to combing with behavioral tests including morris water maze (MWM) or y-maze to determine the role of LC in the therapeutic actions of AD. Network pharmacology was used to screen potential targets and pathways involving in LC's treatments of AD. Western blot was used to detect the phosphorylated expressions of proteins in hippocampus in APP/PS1 mice in the hippocampus. Pharmacological interventions were used to elucidate the relationship between the role of LC in the treatment of AD and the pathway, as well as the upstream and downstream interactions with neuronal activities.

According to our previous LC effective dose (2.5 g/kg), the dose was also able to significantly reduce the latency to the platform, and significantly increase the number of crossing times and time spend in the target quadrant in APP/PS1 mice in MWM, which was consistent with donepezil (DON) after 14 days chronic treatments. Network pharmacology showed that PI3K/AKT and MAPK pathways were closely associated with LC's treatments of AD, and protein autophosphorylation played a role in this process. The phosphorylated expressions of PI3K and AKT were obviously reduced in APP/PS1 mice in the hippocampus, which were both reversed by LC or DON. The phosphorylated expressions of MAPK including P38, JNK and ERK were also significantly reduced in APP/PS1 mice hippocampus, but only the phosphorylated expression of ERK was reversed by LC or DON. Inhibiting the activities of PI3K/AKT pathway by LY294002 blocked LC's improvement of behavioral deficits in APP/PS1 mice, including reducing latency to platform and increasing the number of crossings time in MWM in APP/PS1 mice, which also blunted LC's up-regulated phosphorylated expressions of PI3K, AKT and ERK in the hippocampus. Moreover, suppressing the activities of ERK by PD98059 also blocked LC's improvement of AD-related behavioral deficits including decreasing latency to new arm and increasing time in new arm in y-maze test, which also inhibited LC's enhancement of synaptic proteins (PSD95 and synapsin1) in the hippocampus and the number of EGR1-positive cells in the hippocampal dentate gyrus (DG).

Take together, our study revealed that LC had the therapeutic effects on AD by activating the PI3K/AKT pathway to enhance ERK activity and further strengthened neuronal activities in the hippocampus.

The molecular mechanisms underlying early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) remain incompletely understood, particularly in Asian populations.

RNA-sequencing was carried out on blood samples from 248 participants in the Seoul National University Bundang Hospital cohort to perform differential gene expression (DGE) and weighted gene co-expression network analysis. Findings were replicated in an independent Korean cohort (N = 275).

DGE analysis identified 18 and 88 dysregulated genes in EOAD and LOAD, respectively. Network analysis identified a LOAD-associated module showing a significant enrichment in pathways related to mitophagy, 5' adenosine monophosphate-activated protein kinase signaling, and ubiquitin-mediated proteolysis. In the replication cohort, downregulation of SMOX and PLVAP in LOAD was replicated, and the LOAD-associated module was highly preserved. In addition, SMOX and PLVAP were associated with brain amyloid beta deposition.

Our findings suggest distinct molecular signatures for EOAD and LOAD in a Korean population, providing deeper understanding of their diagnostic potential and molecular mechanisms.

Analysis identified 18 and 88 dysregulated genes in early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD), respectively. Expression levels of SMOX and PLVAP were downregulated in LOAD. Expression levels of SMOX and PLVAP were associated with brain amyloid beta deposition. Pathways including mitophagy and 5' adenosine monophosphate-activated protein kinase signaling were enriched in a LOAD module. A LOAD module was highly preserved across two independent cohorts.

Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington disease, pose serious threats to human health, leading to substantial economic burdens on society and families. Despite extensive research, the underlying mechanisms driving these diseases remain incompletely understood, impeding effective diagnosis and treatment. In recent years, growing evidence has highlighted the crucial role of oxidative stress in the pathogenesis of various neurodegenerative diseases. However, there is still a lack of comprehensive reviews that systematically summarize the impact of mitochondrial oxidative stress on neurodegenerative diseases. This review aims to address this gap by summarizing the molecular mechanisms by which mitochondrial oxidative stress promotes the initiation and progression of neurodegenerative disorders. Furthermore, it discusses the potential of antioxidant-based therapeutic strategies for the treatment of these diseases. By shedding light on the role of mitochondrial oxidative stress in neurodegenerative diseases, this review not only serves as a valuable reference for further research on the disease mechanisms, but also offers novel perspectives for the treatment of these disorders.

Sirtuin-3 (SIRT3) in mitochondria has nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase activity. As such, SIRT3 is crucial in cardiovascular and neurodegenerative diseases. Advanced proteomics and transcriptomics studies have revealed that SIRT3 expression becomes altered when the heart or brain is affected by external stimuli or disease, such as diabetic cardiomyopathy, atherosclerosis, myocardial infarction, Alzheimer's disease, Huntington's disease, and Parkinson's disease. More specifically, SIRT3 participates in the development of these disorders through its deacetylase activity and in combination with downstream signaling pathways. The paper reviews SIRT3's expression changes, roles, and mechanisms associated with the development of cardiovascular and neurodegenerative diseases. Additionally, strategies targeting SIRT3 to treat or regulate cardiovascular and neurodegenerative disease development are discussed.

The steroidogenic acute regulatory (StAR) protein mediates the rate-liming step in neuro/steroid biosynthesis. Multifaceted and delicate changes during aging, disrupting hormonal and neuronal homeostasis, constitute human senescence, an inevitable phenomenon that attributes to increased morbidity and mortality. Aging, along with progressive decreases in bioactive neurosteroids, is the primary risk factor for Alzheimer's disease (AD), which preferentially impacts two-thirds of women and one-third of men. AD is neuropathologically characterized by the accumulation of extracellular amyloid-β and intracellular phosphorylated Tau containing neurofibrillary tangles, resulting in dementia. Postmortem brains pertaining to gender-specific AD patients exhibit varied suppression of StAR and sex neurosteroid levels compared with age-matched cognitively healthy subjects, in which the attenuation of StAR is inversely correlated with the AD pathological markers. Interestingly, retinoid signaling upregulates StAR-motivated neurosteroid biosynthesis and reinstates various neurodegenerative vulnerabilities that promote AD pathogenesis. This review summarizes current understanding of StAR-driven alterations of sex neurosteroids in gender-specific AD risks and provides biochemical and molecular insights into therapeutic interventions for preventing and/or alleviating dementia for healthy aging.

Mitochondrial dysfunction and oxidative stress are critical factors in the pathogenesis of neurodegenerative diseases. The complex interplay between these factors exacerbates neuronal damage and accelerates disease progression. In neurodegenerative diseases, mitochondrial dysfunction impairs ATP production and promotes the generation of reactive oxygen species (ROS). The accumulation of ROS further damages mitochondrial DNA, proteins, and lipids, creating a vicious cycle of oxidative stress and mitochondrial impairment. This review aims to elucidate the mechanisms by which mitochondrial dysfunction and oxidative stress lead to neurodegeneration, and to highlight potential therapeutic targets to mitigate their harmful effects.

In the realm of traditional Chinese medicine, Panax quinquefolius L. has garnered significant attention for its potential to treat various ailments associated with deficiencies, including qi, blood, and kidneys. As its primary bioactive constituent, Panax quinquefolius saponins (PQS) have the potential therapeutic role of Alzheimer's disease (AD) treatment, but with unclear mechanisms of action. Meanwhile, AD is considered as a common dementia disease with kidney insufficiency and deficiency by traditional medicine, and often accompanied by autophagy in modern medical research.

This study aimed to investigate the therapeutic effects of PQS on AD through the regulation of mitophagy.

The chemical constituents of PQS were characterized using the UPLC-QTOF-MS technique. After that, the HT22 cell line was used to establish the D-galactose-induced cell model, and the SAMP8 mice model of AD was also employed. Cell viability was assessed using the CCK-8 assay, ROS detection, JC-1 staining, Mito-tracker Red and LC3 staining, and Mito-tracker Green and Lyso-tracker Red staining were used to assess levels of mitophagy. The Morris Water Maze (MWM) was used for the experimental evaluation of learning and memory abilities in mice. Subsequently, the mechanism was studied by pathological staining and western blotting.

Fifty-eight triterpenoid saponins were identified from PQS, and PQS alleviated D-galactose-induced HT22 cell death and increased intracellular levels of mitochondrial autophagy-related factors. In vivo, PQS significantly improved cognitive deficits and mitigated AD-like pathological features by activating the mitophagy mechanism. Furthermore, PQS may promote Pink1/Parkin-mediated mitophagy by activating the AMPK/mTOR/ULK1/DRP1 and SIRT1/PGC-1α pathways.

In conclusion, PQS have demonstrated the potential to mitigate mitochondrial dysfunction and enhance cognitive function in AD through the activation of mitophagy. This promising strategy holds great promise for the treatment of AD.

Pulmonary arterial hypertension (PAH) is a progressive disorder that can lead to right ventricular failure and severe consequences. Despite extensive efforts, limited progress has been made in preventing the progression of PAH. Mitochondrial dysfunction is implicated in the development of PAH, but the key mitochondrial functional alterations in the pathogenesis have yet to be elucidated.

We integrated three microarray datasets from the Gene Expression Omnibus (GEO), including 222 lung samples (164 PAH, 58 controls), for differential expression and functional enrichment analyses. Machine learning identified key mitochondria-related signaling pathways. PAH and control lung tissue samples were collected, and transcriptomic and metabolomic profiling were performed. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis investigated shared pathways, and canonical correlation analysis assessed gene-metabolite relationships.

In the GEO datasets, mitochondria-related signaling pathways were significantly enriched in PAH samples, in particular the electron transport chain (ETC) in mitochondrial oxidative phosphorylation system. Notably, the electron transport from cytochrome c to oxygen in ETC was identified as the most crucial mitochondria-related pathway, which was down-regulated in PAH samples. Transcriptomic profiling of the clinical lung tissue analysis identified 14 differentially expressed genes (DEGs) related to mitochondrial function. Metabolomic analysis revealed three differential metabolites in PAH samples: increased 3-phenyllactic acid and ADP, and decreased citric acid. Mitochondria-related genes highly correlated with these metabolites included KIT, OTC, CAMK2A, and CHRNA1.

Down-regulation of electron transport from cytochrome c to oxygen in mitochondrial ETC and disruption of the citric acid cycle homeostasis may contribute to PAH pathogenesis. 3-phenyllactic acid emerges as a potential novel diagnostic biomarker for PAH. These findings offer insights for developing novel PAH therapies and diagnostics.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, accounting for approximately 70% of dementia cases worldwide. Patients gradually exhibit cognitive decline, such as memory loss, aphasia, and changes in personality and behavior. Research has shown that mitochondrial dysfunction plays a critical role in the onset and progression of AD. Mitochondrial dysfunction primarily leads to increased oxidative stress, imbalances in mitochondrial dynamics, impaired mitophagy, and mitochondrial genome abnormalities. These mitochondrial abnormalities are closely associated with amyloid-beta and tau protein pathology, collectively accelerating the neurodegenerative process. This review summarizes the role of mitochondria in the development of AD, the latest research progress, and explores the potential of mitochondria-targeted therapeutic strategies for AD. Targeting mitochondria-related pathways may significantly improve the quality of life for AD patients in the future.

Alzheimer's disease (AD) is marked by impaired cognitive functions, particularly in learning and memory, owing to complex and diverse mechanisms. Methionine restriction (MR) has been found to exert a mitigating effect on brain oxidative stress to improve AD. However, the bidirectional crosstalk between the gut and brain through which MR enhances learning and memory in AD, as well as the effects of fecal microbiota transplantation (FMT) from MR mice on AD mice, remains underexplored. In this study, APP/PS1 double transgenic AD mice were used and an FMT experiment was conducted. 16S rRNA gene sequencing, targeted metabolomics, and microbial metabolite short-chain fatty acids (SCFAs) of feces samples were analyzed. The results showed that MR reversed the reduction in SCFAs induced by AD, and further activated the free fatty acid receptors, FFAR2 and FFAR3, as well as the transport protein MCT1, thereby signaling to the brain to mitigate inflammation and enhance the learning and memory capabilities. Furthermore, the FMT experiment from methionine-restricted diet mouse donors showed that mice receiving FMT ameliorated Alzheimer's learning and memory ability through SCFAs. This study offers novel non-pharmaceutical intervention strategies for AD prevention.

Aging presents progressive changes that increase the susceptibility of the central nervous system (CNS) to suffer neurological disorders (NDs). Several studies have reported that an aged brain suffering from NDs shows the presence of pathological forms of tau protein, a microtubule accessory protein (MAP) critical for neuronal function. In this context, accumulative evidence has shown a pivotal contribution of pathological forms of tau to Alzheimer's disease (AD) and tauopathies. However, current investigations have implicated tau toxicity in other NDs that affect the central nervous system (CNS), including Parkinson's disease (PD), Huntington's disease (HD), Traumatic brain injury (TBI), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). These diseases are long-term acquired, affecting essential functions such as motor movement, cognition, hearing, and vision. Previous evidence indicated that toxic forms of tau do not have a critical contribution to the genesis or progression of these diseases. However, recent studies have shown that these tau forms contribute to neuronal dysfunction, inflammation, oxidative damage, and mitochondrial impairment events that contribute to the pathogenesis of these NDs. Recent studies have suggested that these neuropathologies could be associated with a prion-like behavior of tau, which induces a pathological dissemination of these toxic protein forms to different brain areas. Moreover, it has been suggested that this toxic propagation of tau from neurons into neighboring cells impairs the function of glial cells, oligodendrocytes, and endothelial cells by affecting metabolic function and mitochondrial health and inducing oxidative damage by tau pathology. Therefore, in this review, we will discuss current evidence demonstrating the critical role of toxic tau forms on NDs not related to AD and how its propagation and induced-bioenergetics failure may contribute to the pathogenic mechanism present in these NDs.

Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration.