• Allergic rhinitis
• Microglia
• Neuroimmune
• Nose–brain axis
• Olfactory bulb
• Parkinson's disease

• Humans
• Brain/metabolism
• Animals
• Brain Diseases/metabolism
• Brain Diseases/physiopathology
• Nose
• Nose Diseases

• allergic rhinitis
• inflammatory mediators
• neuro-immune
• neurological symptoms
• nose-brain communication

Amyloid-β (Aβ)-peptide production or deposition in the neuropathology of Alzheimer’s disease (AD) was shown to be caused by chronic inflammation that may be induced by infection, but the role of pathogenic-bacteria-related AD-associated Aβ is not yet clearly understood. In this study, we validated the hypothesis that there is a correlation between the Aβ-protein load and bacterial infection and that there are effects of bacteria, Staphylococcus aureus (S. aureus), on the Aβ load in the inflammatory environment of human tonsils. Here, we detected Aβ-peptide deposits in human tonsil tissue as well as tissue similar to tonsilloliths found in the olfactory cleft. Interestingly, we demonstrated for the first time the presence of Staphylococcus aureus (S. aureus) clustered around or embedded in the Aβ deposits. Notably, we showed that treatment with S. aureus upregulated the Aβ-protein load in cultures of human tonsil organoids and brain organoids, showing the new role of S. aureus in Aβ-protein aggregation. These findings suggest that a reservoir of Aβ and pathogenic bacteria may be a possible therapeutic target in human tonsils, supporting the treatment of antibiotics to prevent the deposition of Aβ peptides via the removal of pathogens in the intervention of AD pathogenesis.

The pathological changes of Alzheimer’s disease (AD) begin 10–20 years before clinical onset, and it is therefore desirable to identify effective methods for early diagnosis. The nasal mucosa is a target tissue for measuring AD-related biomarkers because the olfactory nerve is the only cranial nerve that is exposed to the external environment. We describe an autopsy case of rapidly advanced juvenile AD (JAD), focusing on the olfactory system. The formation of senile plaques, neurofibrillary tangles (NFTs), and neuropil threads was examined in the temporal cortex, hippocampus, olfactory bulb, and olfactory and respiratory epithelia in the bilateral olfactory clefts. Neurodegenerative changes in the olfactory and respiratory epithelia and the pathological deposition of amyloid β42 (Aβ42) and phosphorylated tau were also examined. As a result, senile plaques, NFTs, and neuropil threads were found in the temporal cortex, hippocampus, and olfactory bulb. NFTs were also found in the olfactory epithelium. Degenerated olfactory cells and their axons stained positive for phosphorylated tau. Supporting cells in the degenerated olfactory epithelium stained positive for Aβ42. In conclusion, pathological biomarkers of AD were expressed in the degenerated olfactory epithelium of this JAD patient. This observation suggests that nasal samples may be useful for the diagnosis of AD.

• Alzheimer’s Amyloid
• Neurology
• Pathogenesis

• Humans
• Male
• Retrospective Studies
• Amyloid beta-Peptides/metabolism
• Amyloid beta-Peptides/cerebrospinal fluid
• Female
• Aged
• Alzheimer Disease/diagnostic imaging
• Alzheimer Disease/metabolism
• Alzheimer Disease/cerebrospinal fluid
• Nasal Cavity/diagnostic imaging
• Nasal Cavity/metabolism
• Skull Base/diagnostic imaging
• Skull Base/metabolism
• Positron-Emission Tomography
• Cognitive Dysfunction/diagnostic imaging
• Cognitive Dysfunction/metabolism
• Cognitive Dysfunction/cerebrospinal fluid
• Aged, 80 and over
• Aniline Compounds
• Thiazoles
• Middle Aged

We investigated the level of amyloid beta (Aβ) in nasal secretions of patients with Alzheimer’s disease dementia (ADD) using interdigitated microelectrode (IME) biosensors and determined the predictive value of Aβ in nasal secretions for ADD diagnosis. Nasal secretions were obtained from 35 patients with ADD, 18 with cognitive decline associated with other neurological disorders (OND), and 26 cognitively unimpaired (CU) participants. Capacitance changes in IMEs were measured by capturing total Aβ (ΔC_tAβ). After 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) was injected, additional capacitance changes due to the smaller molecular weight Aβ oligomers disassembled from the higher molecular weight oligomeric Aβ were determined (ΔC_oAβ). By dividing two values, the capacitance ratio (ΔC_oAβ/ΔC_tAβ) was determined and then normalized to the capacitance change index (CCI). The CCI was higher in the ADD group than in the OND (p = 0.040) and CU groups (p = 0.007). The accuracy of the CCI was fair in separating into the ADD and CU groups (area under the receiver operating characteristic curve = 0.718, 95% confidence interval = 0.591–0.845). These results demonstrate that the level of Aβ in nasal secretions increases in ADD and the detection of Aβ in nasal secretions using IME biosensors may be possible in predicting ADD.

Cost-effective and feasible methods for early diagnosis of Alzheimer’s disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63–85 years old were recruited in 2015–2016 for this case–control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre-treatment with guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-β (Aβ)₄₂, but no differences in median levels of total tau and Aβ₄₂ between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Aβ₄₂, total tau, and phosphorylated tau, but levels of Aβ₄₀ in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL = 0.52–0.95, p = 0.030) for the middle nasal meatus and 0.72 (95% CL = 0.52–0.92, p = 0.029) for the olfactory cleft. Thus, PGD-I and PGD-II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD.

• Amyloid-β
• biomarker
• nasal smear
• phosphorylated tau
• tau

Dementia, including Alzheimer’s disease, the 21^st Century epidemic, is one of the most significant social and health crises which has currently afflicted nearly 44 million patients worldwide and about new 7.7 million cases are reported every year. This portrays the unmet need towards better understanding of Alzheimer’s disease pathomechanisms and related research towards more effective treatment strategies. The review thus comprehensively addresses Alzheimer’s disease pathophysiology with an insight of underlying multicascade pathway and elaborates possible therapeutic targets- particularly anti-amyloid approaches, anti-tau approaches, acetylcholinesterase inhibitors, glutamatergic system modifiers, immunotherapy, anti-inflammatory targets, antioxidants, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors and insulin. In spite of extensive research leading to identification of newer targets and potent drugs, complete cure of Alzheimer’s disease appears to be an unreached holy grail. This can be attributed to their ineffective delivery across blood brain barrier and ultimately to the brain. With this understanding, researchers are now focusing on development of drug delivery systems to be delivered via suitable route that can circumvent blood brain barrier effectively with enhanced patient compliance. In this context, we have summarized current drug delivery strategies by oral, transdermal, intravenous, intranasal and other miscellaneous routes and have accentuated the future standpoint towards promising therapy ultimately leading to Alzheimer’s disease cure.

• Neurofibrillary tangles
• Alzheimer’s disease
• Dementia
• Amyloid β
• Tau
• Neurodegeneration
• Blood brain barrier
• Transdermal
• Nasal