The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

JOURNAL/nrgr/04.03/01300535-202602000-00047/figure1/v/2025-05-05T160104Z/r/image-tiff Alzheimer's disease is a multi-amyloidosis disease characterized by amyloid-β deposits in brain blood vessels, microaneurysms, and senile plaques. How amyloid-β deposition affects axon pathology has not been examined extensively. We used immunohistochemistry and immunofluorescence staining to analyze the forebrain tissue slices of Alzheimer's disease patients. Widespread axonal amyloidosis with distinctive axonal enlargement was observed in patients with Alzheimer's disease. On average, amyloid-β-positive axon diameters in Alzheimer's disease brains were 1.72 times those of control brain axons. Furthermore, axonal amyloidosis was associated with microtubule-associated protein 2 reduction, tau phosphorylation, lysosome destabilization, and several blood-related markers, such as apolipoprotein E, alpha-hemoglobin, glycosylated hemoglobin type A1C, and hemin. Lysosome destabilization in Alzheimer's disease was also clearly identified in the neuronal soma, where it was associated with the co-expression of amyloid-β, Cathepsin D, alpha-hemoglobin, actin alpha 2, and collagen type IV. This suggests that exogenous hemorrhagic protein intake influences neural lysosome stability. Additionally, the data showed that amyloid-β-containing lysosomes were 2.23 times larger than control lysosomes. Furthermore, under rare conditions, axonal breakages were observed, which likely resulted in Wallerian degeneration. In summary, axonal enlargement associated with amyloidosis, micro-bleeding, and lysosome destabilization is a major defect in patients with Alzheimer's disease. This finding suggests that, in addition to the well-documented neural soma and synaptic damage, axonal damage is a key component of neuronal defects in Alzheimer's disease.

Alzheimer's disease, a devastating neurodegenerative disorder, is characterized by progressive cognitive decline, primarily due to amyloid-beta protein deposition and tau protein phosphorylation. Effectively reducing the cytotoxicity of amyloid-beta42 aggregates and tau oligomers may help slow the progression of Alzheimer's disease. Conventional drugs, such as donepezil, can only alleviate symptoms and are not able to prevent the underlying pathological processes or cognitive decline. Currently, active and passive immunotherapies targeting amyloid-beta and tau have shown some efficacy in mice with asymptomatic Alzheimer's disease and other transgenic animal models, attracting considerable attention. However, the clinical application of these immunotherapies demonstrated only limited efficacy before the discovery of lecanemab and donanemab. This review first discusses the advancements in the pathogenesis of Alzheimer's disease and active and passive immunotherapies targeting amyloid-beta and tau proteins. Furthermore, it reviews the advantages and disadvantages of various immunotherapies and considers their future prospects. Although some antibodies have shown promise in patients with mild Alzheimer's disease, substantial clinical data are still lacking to validate their effectiveness in individuals with moderate Alzheimer's disease.

Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-β and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies.

For many decades, Alzheimer's disease research has primarily focused on impairments within cortical and hippocampal regions, which are thought to be related to cognitive dysfunctions such as memory and language deficits. The exact cause of Alzheimer's disease is still under debate, making it challenging to establish an effective therapy or early diagnosis. It is widely accepted that the accumulation of amyloid-beta peptide in the brain parenchyma leads to synaptic dysfunction, a critical step in Alzheimer's disease development. The traditional amyloid cascade model is initiated by accumulating extracellular amyloid-beta in brain areas essential for memory and language. However, while it is possible to reduce the presence of amyloid-beta plaques in the brain with newer immunotherapies, cognitive symptoms do not necessarily improve. Interestingly, recent studies support the notion that early alterations in subcortical brain regions also contribute to brain damage and precognitive decline in Alzheimer's disease. A body of recent evidence suggests that early Alzheimer's disease is associated with alterations (e.g., motivation, anxiety, and motor impairment) in subcortical areas, such as the striatum and amygdala, in both human and animal models. Also, recent data indicate that intracellular amyloid-beta appears early in subcortical regions such as the nucleus accumbens, locus coeruleus, and raphe nucleus, even without extracellular amyloid plaques. The reported effects are mainly excitatory, increasing glutamatergic transmission and neuronal excitability. In agreement, data in Alzheimer's disease patients and animal models show an increase in neuronal synchronization that leads to electroencephalogram disturbances and epilepsy. The data indicate that early subcortical brain dysfunctions might be associated with non-cognitive symptoms such as anxiety, irritability, and motivation deficits, which precede memory loss and language alterations. Overall, the evidence reviewed suggests that subcortical brain regions could explain early dysfunctions and perhaps be targets for therapies to slow disease progression. Future research should focus on these non-traditional brain regions to reveal early pathological alterations and underlying mechanisms to advance our understanding of Alzheimer's disease beyond the traditionally studied hippocampal and cortical circuits.

Herein, a novel pyrrolo[2,3-b]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, S01, was rationally designed and synthesised to target Alzheimer's disease (AD). S01 inhibited GSK-3β, with an IC50 of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that S01 efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, S01 showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, S01 substantially ameliorated dyskinesia in AlCl3-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of S01 in vivo. Our findings suggested that S01 is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.

Traumatic brain injury and Alzheimer's disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier dysfunction, neuroinflammation, and cognitive deficits. Furthermore, traumatic brain injury can exacerbate Alzheimer's disease-like pathologies, potentially leading to the development of Alzheimer's disease. Nanocarriers offer a potential solution by facilitating the delivery of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease. Unlike traditional approaches to neuroregeneration, this is a molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on the use of nanocarrier systems for the efficient and precise delivery of siRNAs, discussing the advantages, challenges, and future directions. In principle, siRNAs have the potential to target all genes and non-targetable proteins, holding significant promise for treating various diseases. Among the various therapeutic approaches currently available for neurological diseases, siRNA gene silencing can precisely "turn off" the expression of any gene at the genetic level, thus radically inhibiting disease progression; however, a significant challenge lies in delivering siRNAs across the blood-brain barrier. Nanoparticles have received increasing attention as an innovative drug delivery tool for the treatment of brain diseases. They are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier, targeted drug delivery, enhanced drug stability, and multifunctional therapy. The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach. Although this strategy is still in the preclinical exploration stage, it is expected to achieve clinical translation in the future, creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer's disease associated with traumatic brain injury.

The historical pathology of the brain in Alzheimer's disease (AD) is characterized by the amyloid cascade hypothesis, in which amyloid β protein accumulates in the extracellular parenchyma as senile plaque and triggers phosphorylation of microtubule-associated protein tau for forming neurofibrillary tangle in the human neurons. Whether these protein existences differed in the brain parenchyma, the relationship of these proteins of accumulation mechanisms is unknown. In the case of brain pathological analysis, the level of phosphorylation for tau has been decreased in the paraffin-embedded sections compared with biochemical analysis. Here, we have established and developed a method to highlight phosphorylated proteins including tau with frozen sections, as the HIGh Affinity Staining Histological Immunoreactivity (HIGASHI) method. Using this HIGASHI method, hyper-phosphorylated tau could be detected in the mossy fiber on the frozen brain sections of wild-type mice under hypothermia conditions. Here, we attempted the HIGASHI method to detect senile plaque and phosphorylated tau in the AD model mouse brains. Phosphorylated tau was found in the center of senile plaques in the mice brain parenchyma. Additionally, these senile plaques colocalized with microglia cells in the center of senile plaques. Interestingly, senile plaques have been made in the tau knock-out mice brains expressing human amyloid precursor protein. Thus, senile plaques have been composed of Aβ and phosphorylated tau in the brain, but tau isn't necessary for bearing senile plaques.

Alzheimer's disease (AD) is a complex neurodegenerative disorder and the leading cause of dementia in the elderly, as classified by the WHO. Its neuropathological hallmarks include the accumulation of amyloid-β (Aβ) plaques and intracellular tau tangles, which contribute to oxidative stress, mitochondrial dysfunction, lipid peroxidation, and neuronal death. Emerging evidence suggests that melatonin, a potent antioxidant produced by the pineal gland, plays a neuroprotective role in AD, yet its precise mechanisms remain underexplored. In this study, we utilized a physiologically relevant primary culture of hippocampal neurons to investigate melatonin's protective effects against toxicity induced by Aβ25-35. Our findings demonstrate that melatonin significantly enhances cellular metabolism and viability while reducing reactive oxygen species (ROS) levels and lipid peroxidation, thereby mitigating Aβ-induced neurotoxicity. These results provide mechanistic insights into melatonin's antioxidative and neuroprotective properties, reinforcing its potential as a therapeutic agent against oxidative stress in AD. This study underscores the promise of melatonin-based interventions in the development of novel antioxidant-targeted therapies for AD.

The adapter protein KINDLIN2, encoded by the Alzheimer's disease (AD) genetic risk factor FERMT2, was identified as a modulator of APP processing. KINDLIN2 directly interacts with APP to modulate its metabolism, and KINDLIN2 underexpression impairs long-term potentiation in an APP-dependent manner. Altogether, these data suggest that loss of KINDLIN2 could have a detrimental effect on synaptic function and promote AD pathophysiological process. In this study, we identified KINDLIN2 as a novel substrate of caspases and calpain I, two well-characterized cysteine proteases involved in the regulation of synaptic plasticity. These cleavages resulted in the dissociation of the F0 and F1 domains of KINDLIN2 that are necessary for it to function as an adapter protein. Furthermore, we demonstrate that these cleavages lead to a decrease in KINDLIN2's ability to control APP processing. Overall, these KINDLIN2 cleavages appear as potential new mechanisms in the regulation of KINDLIN2 functions at the synapse and could be of interest for the pathophysiology of AD.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques, which serve as crucial biomarkers for disease diagnosis and therapeutic evaluation. While fluorescence imaging has emerged as a powerful technique for Aβ detection, current probes face limitations in clinical application due to insufficient photostability and short blood half-life, resulting in compromised signal-to-noise ratios (SNRs) and imaging resolution. Herein, two bright quinoxalinone-based fluorescent probes (QNO-AD-PEGs) were presented, which incorporate hydrophilic poly(ethylene glycol) (PEG) chains for enhanced biocompatibility and an Aβ-specific N,N-dimethylaminophenyl recognition unit. QNO-AD-PEG1 demonstrated exceptional binding affinity for Aβ42 aggregates (Kd = 42 nM) and a remarkable 49-fold fluorescence enhancement upon target engagement, with a quantum yield (ΦAβ) of 11.45%. In vivo imaging revealed that QNO-AD-PEG1 effectively crossed the blood-brain barrier (BBB) and exhibited a prolonged half-life (315 min). Notably, the probe successfully visualized age-dependent Aβ plaque progression in AD mouse models. This study presents a significant breakthrough in molecular imaging for neurodegenerative diseases, offering a versatile tool for both fundamental AD research and potential clinical applications.

We report the first molecular dynamics simulations to examine the effect of pH on the structure, dynamics, and metal-binding ability of amyloid-β, the peptide implicated in the onset of Alzheimer's disease. We show that in the pH range of 6 to 8 only histidine residues show variable protonation, that predicted pKa values are in agreement with experimental data, and that changes in pH affect the size, flexibility, and secondary structure of the peptide. The binding of Cu(II) or Zn(II) to the peptide induces a shift of 1 to 1.5 pKa units in unbound histidine residues, while metal binding modes associated with higher pH induce significant changes in peptide structure. We speculate on the significance of these findings on results showing pH dependence as well as on Cu(II) and Zn(II) modulation of aggregation of Amyloid-β.

Poor vascular function and reduced nitric oxide (NO)-bioavailability have been recognized to be involved in aging and Alzheimer's Disease (AD). A non-pharmacological treatment that is gaining clinical interest in the context of vascular function is dietary inorganic nitrate (NO3-) supplementation which increases NO-bioavailability through the NO3- -nitrite (NO2-) - NO pathway. This treatment has been demonstrated to improve vascular function in several clinical populations, but no study has investigated the effects in individuals with AD. Therefore, changes in plasma NO3- and NO2- and vascular responsiveness (hyperemic response to single-passive leg movement (ΔPLM)) were measured in individuals with AD (n = 10, 76 ± 9 years), healthy elderly (OLD, n = 10, 75 ± 6 years), and young individuals (YN, n = 10, 25 ± 4 years) before (T0) and hourly for 4 h (T1, T2, T3, and T4) after ingestion of either NO3--rich beetroot juice (BR) or a placebo (PLA). No changes in NO3- and NO2-, nor ΔPLM were detected in any group following PLA intake. Plasma NO3- and NO2- increased significantly in all three groups at T1 (p < 0.001) and remained elevated for the rest of the trial. The same trend was found in ΔPLM, which significantly increased in all three groups over the time (p < 0.001). However, AD exhibited significantly lower ΔPLM values at any time point compared to YN (p < 0.001) and OLD (p < 0.001). These data suggest that AD-individuals included in this study were able to reduce NO3- to NO2- and to increase NO-mediated vascular responsiveness as non-AD-individuals. Other mechanisms, beyond NO-bioavailability, may be involved in vascular dysfunction in patients with AD. This research suggests that an acute administration of inorganic nitrate is not enough to revert chronically adapted vascular properties and completely restore vascular responsiveness in AD.

The purpose of this study was to advance our understanding of the neurobiology of healthy aging, which is crucial for improving quality of life and preventing age-related diseases. Despite its importance, a comprehensive investigation of this process has yet to be fully characterized.

We used a hybrid PET/MRI scanner to assess neurophysiological parameters in 80 healthy individuals aged 20-78. Cerebral amyloid-beta (Aβ) deposition and glucose metabolism were assessed using PET scans, while participants underwent simultaneous MRI scans.

We found a positive correlation between Aβ-deposition and aging, and a negative correlation between glucose metabolism and aging. The insula showed the strongest negative correlation between glucose metabolism and age (Spearman's r = -0.683, 95% CI [-0.79, -0.54], p < 0.0001), while the posterior cingulate cortex had the strongest positive correlation between Aβ-deposition and age (Spearman's r = 0.479, 95% CI [0.28, 0.64], p < 0.0001). These results suggest a spatially dependent link between Aβ-deposition and metabolism in healthy older adults, indicating a compensatory mechanism in early Alzheimer's. Additionally, Aβ-deposition was linked to changes in interregional neural communication.

Our study confirms previous findings on aging and offers new insights, particularly on the role of Aβ-deposition in healthy aging. We observed a linear increase in Aβ-deposition, alongside decreases in white matter integrity, cerebral blood flow, and glucose metabolism. Additionally, we identified a complex regional relationship between Aβ-deposition, glucose metabolism, and neural communication, possibly reflecting compensatory mechanisms.

Alzheimer's disease (AD) is a progressive neurodegenerative condition that creates a significant global health challenge and profoundly affects patients and their families. Recent research has highlighted the critical role of microorganisms, particularly viral infections, in the pathogenesis of AD. The involvement of viral infections in AD pathogenesis is predominantly attributed to their ability to induce neuroinflammation and amyloid beta (Aβ) deposition in the brain. The extant research exploring the relationship between viruses and AD has focused largely on Herpesviridae family. Traces of Herpesviruses, such as Herpes Simplex Virus-1 and Epstein Barr Virus, have been found in the brains of patients with AD. These viruses are thought to contribute to the disease progression by triggering chronic inflammatory responses in the brain. They can remain dormant in the brain, and become reactivated due to stress, a secondary viral infection, or immune-senescence in older adults. This review focuses on the association between Herpesviridae and bacterial infections with AD. We explore the genetic factors that might regulate viral illness and discuss clinical trials investigating antiviral and anti-inflammatory agents as possible therapeutic strategies to mitigate cognitive decline in patients with AD. In summary, understanding the interplay between infections, genetic factors, and AD pathogenesis may pave the way for novel therapeutic approaches, facilitating better management and possibly even prevent this debilitating disease.

The "amyloid cascade hypothesis" for Alzheimer's disease (AD) pathogenesis, highlights the accumulation of amyloid-β (Aβ) as a crucial trigger for the pathology. However, AD is an extremely complex disease influenced by multiple pathophysiological processes, making it impossible to attribute its onset to a single hypothesis. The endocytic pathway, where the amyloidogenic processing of APP occurs, has emerged as a pathogenic "hub" for AD. In this study, we found altered homeostasis and dynamics of endolysosomal compartments in fibroblasts from patients affected by a genetic form of AD (APP V717I mutation). These alterations corresponded to an abnormal trafficking of APP along the endolysosomal pathway, favouring its amyloidogenic processing. The identification of APP interactors involved in its trafficking and processing, and finding molecules able to interfere with these interactions, represents a promising therapeutic approach. However, the role of endosomal pathway and the possibility of modulating APP processing through it remains elusive. Among the proteins participating to APP metabolism, the RPSA receptor and its inhibitor molecule NSC47924 have been identified. In this study, we found that the inhibitor, likely by displacing APP from interaction with its receptor, reduced APP accumulation in EEs in AD cells, finally restoring both endosomal dynamics and APP distribution to those of unaffected cells. We also demonstrated that RPSA inhibition affected the aberrant APP cleavage, as it reduced the production of both APP-βCTF (C-Terminal Fragment) and Aβ in AD fibroblasts. These results highlight significant differences in endolysosomal compartments and APP processing in AD-affected cells, refining our understanding of APP/RPSA intersection.

Magnetic resonance imaging (MRI), combined with artificial intelligence techniques, has improved our understanding of brain structural change and enabled the estimation of brain age. Neurodegenerative disorders, such as Alzheimer's disease (AD), have been linked to accelerated brain aging. In this study, we aimed to develop a deep-learning framework that processes and integrates MRI images to more accurately predict brain age, cognitive function, and amyloid pathology.

In this study, we aimed to develop a deep-learning framework that processes and integrates MRI images to more accurately predict brain age, cognitive function, and amyloid pathology.We collected over 10,000 T1-weighted MRI scans from more than 7,000 individuals across six cohorts. We designed a multi-modal deep-learning framework that employs 3D convolutional neural networks to analyze MRI and additional neural networks to evaluate demographic data. Our initial model focused on predicting brain age, serving as a foundational model from which we developed separate models for cognition function and amyloid plaque prediction through transfer learning.

The brain age prediction model achieved the mean absolute error (MAE) for cognitive normal population in the ADNI (test) datasets of 3.302 years. The gap between predicted brain age and chronological age significantly increases while cognition declines. The cognition prediction model exhibited a root mean square error (RMSE) of 0.334 for the Clinical Dementia Rating (CDR) regression task, achieving an area under the curve (AUC) of approximately 0.95 in identifying ing dementia patients. Dementia related brain regions, such as the medial temporal lobe, were identified by our model. Finally, amyloid plaque prediction model was trained to predict amyloid plaque, and achieved an AUC about 0.8 for dementia patients.

These findings indicate that the present predictive models can identify subtle changes in brain structure, enabling precise estimates of brain age, cognitive status, and amyloid pathology. Such models could facilitate the use of MRI as a non-invasive diagnostic tool for neurodegenerative diseases, including AD.

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.

Anti-amyloid antibodies for the treatment of Alzheimer´s disease (AD) are currently being evaluated for approval and reimbursement in Europe. An approval brings opportunities, but also challenges to health care systems across Europe. The objective of this position paper is to provide guidance from experts in the field in terms of navigating implementation.

Members of the European Alzheimer's Disease Consortium and a representative of Alzheimer Europe convened to formulate recommendations covering key areas related to the possible implementation of anti-amyloid antibodies in AD through online discussions and 2 rounds of online voting with an 80% threshold for a position to be accepted.

In total, 24 recommendations were developed covering the research landscape and priorities within research in AD following a possible approval, potential impact on health care systems and diagnostic pathways, and communication to patients about anti-amyloid antibodies. Anti-amyloid antibodies are regarded as a substantial innovation with an important clinical impact. In addition, however, new compounds with other mechanisms of action and/or route of administration are also needed. Approval of new treatments will require changes to existing patient pathways and real-world data needs to be generated.

Comprehensive guidance is provided on the potential implementation of anti-amyloid antibody therapies in Europe following possible approval. Emphasis is placed on the necessity of regularly updating recommendations as new evidence emerges in the coming years.

The 2024 Lancet Commission estimates 45% of dementias worldwide are preventable if 14 potentially modifiable risk factors for dementia were eliminated. While this is unlikely, there is evidence that even modest risk factor reduction will have significant benefits. Whether this is best achieved at the level of the individual or broader population level approaches is the purpose of this review.

To date, evidence for the efficacy of individual-level interventions in preventing cognitive decline or dementia is modest at best. Reasons for this include the sociodemographic and risk profile of study participants and complex disease causes, while overlooking the underlying social and commercial determinants of health influencing risk exposure. There is, however, growing evidence supporting population-level approaches to dementia risk reduction. Trend studies from high-income countries showing declines in dementia incidence over recent decades suggest their effectiveness.

The limited evidence for the efficacy, let alone effectiveness, of individual-level interventions is in part because they operate within the influence of social and commercial determinants of health. For significant and sustained risk factor reduction, population-level interventions targeting the underlying determinants of risk factor exposure across the life course, with sensitivity to diverse contexts, are required.

: Alzheimer's disease (AD) is a neurodegenerative disorder closely associated with aging, and its pathogenesis involves the interaction of multidimensional pathophysiologic processes. This review outlines the core mechanisms linking aging and AD. The amyloid cascade hypothesis emphasizes that abnormal deposition of amyloid-β (Aβ) triggers neuronal damage and synaptic dysfunction, which is exacerbated by aging-associated declines in protein clearance. Neuroinflammation, a synergistic pathogenetic factor in AD, is mediated by microglia activation, creating a vicious cycle with Aβ and tau pathology. The cholinergic hypothesis states that the degeneration of cholinergic neurons in the basal forebrain can lead to acetylcholine deficiency, which is directly associated with cognitive decline. Endothelial disorders promote neuroinflammation and metabolic waste accumulation through blood-brain barrier dysfunction and cerebral vascular abnormalities. In addition, glutamate-mediated excitotoxicity and mitochondrial dysfunction (e.g., oxidative stress and energy metabolism imbalance) further lead to neuronal death, and aging-associated declines in mitochondrial autophagy exacerbate such damage. This review also explores the application of animal models that mimic AD and aging in studying these mechanisms and summarizes therapeutic strategies targeting these pathways. Future studies need to integrate multi-targeted therapies and focus on the role of the aging microenvironment in regulating AD pathology in order to develop more effective early diagnosis and treatment options.

Hippocampal interneurons (INs) play a fundamental role in regulating neural oscillations, modulating excitatory circuits, and shaping spatial representation. While historically overshadowed by excitatory pyramidal cells in spatial coding research, recent advances have demonstrated that inhibitory INs not only coordinate network dynamics but also contribute directly to spatial information processing. This review aims to provide a novel integrative perspective on how distinct IN subtypes participate in spatial coding and how their dysfunction contributes to cognitive deficits in neurological disorders such as epilepsy, Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral hypoxia-ischemia. We synthesize recent findings demonstrating that different IN classes-including parvalbumin (PV)-, somatostatin (SST)-, cholecystokinin (CCK)-, and calretinin (CR)-expressing neurons-exhibit spatially selective activity, challenging traditional views of spatial representation, and influence memory consolidation through network-level interactions. By leveraging cutting-edge techniques such as in vivo calcium imaging and optogenetics, new evidence suggests that INs encode spatial information with a level of specificity previously attributed only to pyramidal cells. Furthermore, we investigate the impact of inhibitory circuit dysfunction in neurological disorders, examining how disruptions in interneuronal activity lead to impaired theta-gamma coupling, altered sharp wave ripples, and destabilized place cell representations, ultimately resulting in spatial memory deficits. This review advances the field by shifting the focus from pyramidal-centered models to a more nuanced understanding of the hippocampal network, emphasizing the active role of INs in spatial coding. By highlighting the translational potential of targeting inhibitory circuits for therapeutic interventions, we propose novel strategies for restoring hippocampal network function in neurological conditions. Readers will gain a comprehensive understanding of the emerging role of INs in spatial representation and the critical implications of their dysfunction, paving the way for future research on interneuron-targeted treatments for cognitive disorders.

Inhibition of amyloid precursor protein (APP) beta-site cleaving enzyme 1 (BACE1) has been a target for Alzheimer's disease (AD) therapeutic development. Here, we report our identification of APP-selective BACE1 (ASBI) inhibitors that are selective for APP as the substrate and BACE1 as the target enzyme. A known fluoro aminohydantoin (FAH) inhibitor compound was identified by screening a compound library for inhibition of BACE1 cleavage of a maltose binding protein (MBP)-conjugated-APPC125 substrate followed by optimization and IC50 determination using the P5-P5' activity assay. Optimization of the screening hit led to candidate FAH65, which displays selectivity for inhibition of APP cleavage with little activity against other BACE1 substrates neuregulin 1 (NRG1) or p-selectin glycoprotein ligand-1 (PSGL1). FAH65 shows little inhibitory activity against other aspartyl proteases cathepsin D (Cat D) and BACE2. FAH65 reduces BACE1 cleavage products soluble APPβ (sAPPβ) and the β C-terminal fragment (βCTF), as well as amyloid-β (Aβ) 1-40 and 1-42, both in vitro in cells and in vivo in an animal model of AD. In a murine model of AD, FAH65 improved the discrimination score in the Novel Object Recognition (NOR) memory testing paradigm. The active enantiomer of racemate FAH65, FAH65E(-), displays good brain-penetrance and target engagement, meriting further pre-clinical development as an ASBI that may reduce Aβ levels and overcome the deleterious effects of the non-selective BACE1 inhibitors that have failed in the clinic. FAH65E(-) has the potential to be a first-in-class oral therapy that could be used in conjunction with an approved anti-Aβ antibody therapy for AD.

Natural products derived from traditional Chinese medicine have received significant attention as potential treatments for neurodegenerative disorders due to their wide availability, demonstrated efficacy, and favorable safety profiles. Intranasal delivery provides distinct advantages for targeting the central nervous system (CNS), enabling direct therapeutic agent delivery to the brain by bypassing the blood-brain barrier (BBB). This review evaluates natural products administered intranasally for neurodegenerative diseases (NDs), highlighting their therapeutic potential and addressing formulation challenges related to physicochemical properties. Strategic optimization approaches are proposed, including novel carrier systems, molecular modifications, and combination therapies. By discussing current difficulties and offering practical recommendations, this review aims to encourage further scholarly research and clinical application.

Epimedium brevicornu Maxim, a Chinese herbal medicine, is known for its efficacy in nourishing the kidneys. Icariin (ICA), the primary active ingredient in Epimedium brevicornu Maxim., possesses multiple pharmacological properties, yet its impact on Alzheimer's disease (AD) warrants further exploration.

Study aims to explore the inhibitory impact of ICA on neuroinflammation in AD via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway.

SPF-grade male ICR mice were used to establish an AD model by lateral ventricle injection of Aβ1-42. Behavioral, pathological assessments, as well as immunofluorescence staining, molecular docking, and Western blot analyses, were conducted to evaluate the effects of ICA treatment on memory function, neuronal damage, neuroinflammation, and the cGAS- STING pathway in mice.

ICA significantly improved memory impairment, alleviated neuronal damage and apoptosis, and suppressed neuroinflammation in AD mice. Additionally, ICA inhibited microglial hyperactivation, promoting the transition from the M1 to the M2 phenotype. It specifically inhibited the activation of the cGAS-STING pathway and down-regulated the expression of cGAS, STING, p-TBK1/TBK1, p-IRF3/IRF3 and p-NF-κB/NF-κB. Furthermore, molecular docking revealed that the binding energy between ICA and cGAS was -7.07 kcal/mol, indicating a stable interaction. Further validation using the cGAS-selective small molecule inhibitor RU.521 confirmed the protective effects of ICA against cGAS-STING signaling on microglial transformation and neuroinflammation.

ICA exhibits therapeutic potential in AD by inhibiting microglial transformation and neuroinflammation through the cGAS-STING pathway, positioning it as a candidate drug for AD treatment targeting this pathway.

The amyloid cascade hypothesis predicts that amyloid-beta (Aβ) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aβ40 and Aβ42 and total Tau (t-Tau) plasma biomarkers. Plasma Aβ40, Aβ42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aβs and t-Tau. No clear evidence that Aβ40 or Aβ42 directly causes t-Tau was observed. Instead, the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aβ biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. Plasma Aβ40 or Aβ42 do not appear to have a direct causal impact on t-Tau, though our use of total rather than phosphorylated tau was a limitation. In contrast, Aβ biomarkers appeared to causally impact NFL in cognitively unimpaired men in their late 60 s.

As an important bioactive substance in cells, nicotinamide mononucleotide (NMN) has been proven to play an important role in antiaging, treatment of neurodegenerative diseases, and cardioprotection. It presents a high potential for application in the research fields of functional foods, cosmetics, healthcare products, and active pharmaceuticals. With the increased demand, whether NMN can achieve large-scale industrial production has been a wide concern. The chemical synthesis method of NMN mainly faces the problems of separation, purification, and complex process control; in contrast, biosynthesis methods such as microbial fermentation and enzyme catalysis are considered to be the mainstream of the future industrial production of NMN due to the advantages of environmental friendliness, high efficiency, and simple separation. This review first describes the physiological functions of NMN and the related areas of its applications. Subsequently, it focuses on the research progress on different synthetic pathways of NMN in biosynthetic approaches, mining and modification of key enzymes, chassis cell design and optimization, and whole-cell catalysis. Meanwhile, the regulatory strategies, methods, and process control of the microbial synthesis of NMN are also elaborated, and the synthesis efficiencies of different chassis cells are systematically compared. Finally, this review summarizes the existing problems and challenges of microbial synthesis of NMN and proposes future strategies and directions to address these issues. This work provides technical references and a theoretical basis for researching efficient NMN microbial synthesis and application.

Two thirds of Alzheimer's disease (AD) patients are female. Genetic and chronic health risk factors for AD affect females more negatively compared to males.

This multimodal neuroimaging study aimed to examine sex differences in cognitively unimpaired older adults on: (1) amyloid-β via 18F-AV-45 Florbetapir PET imaging, (2) neurodegeneration via T1 weighted MRI volumetrics, (3) cerebral blood flow via ASL-MRI. We identified AD risk factors including genetic (APOE genotype status) and health markers (fasting glucose, mean arterial pressure, waist-to-hip ratio, and android and gynoid body fat) associated with neuroimaging outcomes for which we observed sex differences.

Participants were sedentary, amyloid-β positive older adults (N = 112, ages 65-87 years) without evidence of cognitive impairment (CDR = 0).

Multivariate analysis of covariance models adjusted for intracranial volume, age, and years of education demonstrated lower volume [F (7, 102) = 2.67, p = 0.014] and higher blood flow F (6, 102) = 4.25, p ≤ 0.001) among females compared to males in regions of interest connected to AD pathology and the estrogen receptor network. We did not observe sex differences in amyloid-β levels. Higher than optimal waist to hip ratio was most strongly associated with lower volume among female participants.

Findings suggest genetic and chronic health risk factors are associated with sex-specific AD neuroimaging biomarkers. Underlying sex-specific biological pathways may explain these findings. Our results highlight the importance of considering sex differences in neuroimaging studies and when developing effective interventions for AD prevention and risk reduction.

Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive dementia and brain accumulation of Aβ-peptide-containing plaques, gliosis, neuroimmune changes, and neurofibrillary tangles. Mushroom polysaccharides have been previously reported to have anti-neuroinflammation activity through the gut-brain axis. This study aimed to evaluate whether a dietary intervention with Phallus atrovolvatus, a recently identified edible mushroom in Thailand, could have a benefit on gut health and alleviate AD-related changes. Methods: Male and female 6-8-month-old littermate wild-type control (C57BL/6J) and AppNL-G-F mice were randomly assigned to either a control diet or a diet supplemented with mushroom aqueous extract (MAE) for 8 weeks to quantify changes in body weight, intestine, immune cells, short chain fatty acids, brain cytokines, amyloid-β (Aβ) levels, gliosis, and memory. Results: MAE had no adverse effects on gut leakiness and increased pyruvate levels in serum. Splenocyte immune profiling revealed a significant increase in the frequency of IgM+, IA_IE+, and CD14+ cells in MAE-administered AppNL-G-Ffemale mice compared to their vehicle controls. AppNL-G-Fmale mice that received MAE showed a significant increase in the frequency of cytotoxic CD8 T cells within the cervical lymph nodes compared to their wild-type counterparts. Aβ deposition and gliosis were significantly reduced in the hippocampi of the MAE-supplemented AppNL-G-F groups. However, MAE feeding did not alter spatial recognition memory in either sex or genotype compared to their vehicle groups. Conclusions: Our findings demonstrated that the administration of P. atrovolvatus aqueous extract showed neuroprotective potential against AD-related changes in the brain with no adverse impact on gut health and memory.

Although the causes of Alzheimer's disease (AD) are still unknown, the unfolded protein response (UPR) is considered the basis for the pathogenesis of many degenerative diseases, including AD. The incidence of AD is slightly higher in the female population; however, biases continue to raise questions as to whether gender is a risk factor for the disease, as insulin resistance is. In this study, we used a sporadic model of Alzheimer's disease, induced by intracerebroventricularly-administered streptozotocin (STZ) in Wistar rats, to evaluate potential modulations in proteins involved in the UPR and the dependence of alterations on the sex of the animals. The rats were evaluated at two time points; 4 and 16 weeks post-STZ. At 16 weeks, cognitive deficit was observed in all rats treated with STZ, as well as an increase in glial fibrillary acid protein (GFAP), and a reduction in synaptophysin in the hippocampus. However, at 4 weeks, cognitive deficit was found only in males, in association with a reduction in synaptophysin. With regard to neurochemical changes in the AD model of STZ, we found sex-dependent differences in the gene expression of OASIS (an ATF-6-like UPR sensor in astrocytes), calpastatin (inhibitor protein of calpain 1/2), calpain-10, calcineurin, sorcin and CHOP. Taken together, results obtained herein contribute to the understanding of the pathogenesis of AD and indicate that the STZ-triggered UPR observed may be sex-dependent.

Neuroinflammation plays a crucial role in Alzheimer's disease (AD) pathogenesis. We investigated the relationship between cerebrospinal fluid (CSF) C-C chemokine ligand 25 (CCL25), an inflammatory regulator, and AD pathology and progression. We analyzed data on CSF CCL25, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated tau [pTau]181, amyloid positron emission tomography [PET]), postmortem neuropathology, magnetic resonance imaging-based neurodegeneration, and cognitive function from 703 participants in the Alzheimer's Disease Neuroimaging Initiative cohort. We found that elevated CSF CCL25 levels were associated with cognitive impairment, abnormal Aβ and tau pathology, greater brain atrophy, and worse cognitive performance (all P < 0.05). Notably, CSF CCL25 exhibited nonlinear relationships with Aβ and tau pathology, reaching a plateau as AD pathology increased. CSF CCL25 showed acceptable diagnostic accuracy in distinguishing amyloid-positive/negative (A ±) and tau-positive/negative (T ±) participants (area under the curve [AUC] = 0.71-0.77) and autopsy-confirmed AD cases (AUC = 0.77), with optimal performance in differentiating A + T + from A-T- participants (AUC = 0.82-0.85 with age and sex adjustment). Longitudinally, higher baseline CSF CCL25 predicted accelerated amyloid accumulation, hippocampal atrophy, and cognitive decline. Mediation analyses revealed that CCL25 partially mediated associations between Aβ pathology and tau pathology (mediating effect: 54.5%), neurodegeneration (18.2%), and cognitive decline (7.4%). Among 37 CSF CCL and CXCL chemokines examined, 28 were associated with at least one AD-related outcome, with CCL25 demonstrating the strongest associations overall. These findings suggest that CSF CCL25 is involved in early AD pathological progression and may serve as an inflammatory biomarker for diagnosis and monitoring of disease progression in AD.

Rho-associated protein kinase 2 (ROCK2) is a serine/threonine kinase that is crucial for regulating various physiological processes and is part of the Rho-associated coiled-coil kinase family. The dysregulation of ROCK2 has been associated with a range of diseases, making it a promising target for therapy. In this study, a chemical feature-based pharmacophore model was developed on the co-crystal ligand (5YS) of ROCK2 to conduct the virtual screening of ZINC database, resulting in 4809 hits that were further subjected to molecular docking to find the binding affinities with ROCK2 protein. The binding affinities of the hits were analyzed and compounds in the range of -11.55 to -9.91 kcal/mol were selected for further analysis. The ADMET analysis identified two promising compounds, whose binding stability with the ROCK2 protein was further evaluated using molecular dynamics (MD) simulations. Simulation results revealed that the selected compounds remained closely bound to protein indicating that they can act as lead compounds to control the biological activity of ROCK2. However, further in vitro investigation is required to test the biological efficacy of the reported compounds.

Dementia with Lewy bodies (DLB) frequently coexists with Alzheimer's disease pathology, yet the pattern of cortical microstructural injury and its relationship with amyloid, tau, and cerebrovascular pathologies remains unclear. We applied neurite orientation dispersion and density imaging (NODDI) to assess cortical microstructural integrity in 57 individuals within the DLB spectrum and 57 age- and sex-matched cognitively unimpaired controls by quantifying mean diffusivity (MD), tissue-weighted neurite density index (tNDI), orientation dispersion index (ODI), and free water fraction (FWF). Amyloid and tau levels were measured using PiB and Flortaucipir PET imaging. Compared to controls, DLB exhibited increased MD and FWF, reduced tNDI across multiple regions, and focal ODI reductions in the occipital cortex. Structural equation modeling revealed that APOE genotype influenced amyloid levels, which elevated tau, leading to microstructural injury. These findings highlight the role of AD pathology in DLB neurodegeneration, advocating for multi-target therapeutic approaches addressing both AD and DLB-specific pathologies.

The piperazine derivative N-(2,6-difluorophenyl)-2-(4-phenylpiperazin-1-yl)propanamide (cmp2) has emerged as a potential transient receptor potential cation channel, subfamily C, member 6 (TRPC6) modulator, offering a promising pathway for Alzheimer's disease (AD) therapy. Our recent findings identify cmp2 as a novel compound with synaptoprotective effects in primary hippocampal cultures and effective blood-brain barrier (BBB) penetration. In vivo studies demonstrate that cmp2 (10 mg/kg, intraperitoneally) restores synaptic plasticity deficits in 5xFAD mice. This study further shows cmp2's selectivity towards tetrameric TRPC6 channel in silico. Acute administration of cmp2 is non-toxic, with no indications of chronic toxicity, and Ames testing confirms its lack of mutagenicity. Behavioral assays reveal that cmp2 improves cognitive functions in 5xFAD mice, including increased novel object recognition, better passing of the Morris water maze, and improved fear memory, as well as upregulation of motor function in beam walking tests. These findings suggest that cmp2 holds promise as a candidate for AD treatment.

The formation of amyloid beta (Aβ) plaques is a central process in the development of Alzheimer's disease (AD). Although its causative role or the effectiveness of therapeutic targeting is still debated, the key involvement of Aβ in the pathogenesis of neuroinflammation and neurodegeneration in AD is broadly accepted. In this review, we emphasize the role of lipid rafts, both in APP cleavage producing Aβ in neurons and in mediating Aβ inflammatory signaling in microglia. We introduce the term inflammarafts to characterize the Aβ-driven formation of enlarged, cholesterol-rich lipid rafts in activated microglia, which support protein-protein and lipid-protein interactions of inflammatory receptors. Examples reviewed include toll-like receptors (TLR2, TLR4), scavenger receptors (CD36, RAGE), and TREM2. The downstream pathways lead to the production of cytokines and reactive oxygen species, intensifying neuroinflammation and resulting in neuronal injury and cognitive decline. We further summarize emerging therapeutic strategies and emphasize the utility of apolipoprotein A-I binding protein (AIBP) in selective targeting of inflammarafts and attenuation of microglia-driven inflammation. Unlike the targeting of a single inflammatory receptor or a secretase, selective disruption of inflammarafts and preservation of physiological lipid rafts offer a novel approach to targeting multiple components and processes that contribute to neuroinflammation in AD.

Peptide inhibitor design targeting self-assembly of amyloid-β (Aβ) represents a promising strategy for suppressing the pathogenic mechanism of Alzheimer's disease (AD). Conventional approaches have primarily mimicked repetitive sequences found in fibrillar structures of Aβ aggregates. However, since the inherent flexibility of Aβ structures promotes the structural changes in the early-stage oligomerization, a structural modulation should be considered in the design of peptide inhibitors. Herein, we introduce topological reprogramming of peptides to control the structural transformation in pathogenic Aβ 1-42 (Aβ42). The eleven-residue peptide scaffold Pa11 (14HQKLVNFAEDV24) identified through the initial screening was dimerized via a disulfide bond. The dimerization stabilizes Aβ42 into higher order structures by promoting antiparallel β-sheet conformations, thereby significantly suppressing Aβ42 aggregation. Our approach underscores that modification in peptide connectivity would be a breakthrough for controlling the intrinsic flexibility of Aβ, surpassing the limitation in conventional, one-dimensional peptide building block.

SIRT3, a crucial deacetylase that plays a key role in regulating mitochondrial acetylation, is tightly linked to metabolic processes and is essential for the maintenance of eukaryotic life. SIRT3 is a potential therapeutic target due to its key role in various diseases, including ageing, heart disease, cancer, and metabolic disorders. In this work, we aimed to identify potential SIRT3 inhibitors from the deep-sea fungal metabolites by employing molecular docking and ADMET analysis. Based on the binding affinities, ten compounds were selected whose docking scores were in the range of -9.693 to -8.327 kcal/mol. Further, four compounds Penipanoid C, Penicillactam, Quinolonimide, and Brevianamide R were selected based on the ADMET properties and subjected to Molecular dynamics simulations to assess the stability of these molecules with target. The stability analysis indicated that the selected compounds could act as lead compounds during in vitro assays to advance these drug candidates towards clinical drug development.