Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid beta (Abeta) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Abeta production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.
Alzheimer Disease/immunology/pathology/*therapy ; Amyloid beta-Peptides/antagonists & inhibitors/immunology/metabolism ; Antibodies, Monoclonal/therapeutic use ; Brain/metabolism/pathology ; Humans ; Immunotherapy ; N-Methylaspartate/therapeutic use ; tau Proteins/antagonists & inhibitors/metabolism

No abstract available.
Humans ; Neurodegenerative Diseases/*drug therapy/*etiology

Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.
Animals ; DNA, Mitochondrial/*genetics ; Humans ; Mitochondria/drug effects/genetics/metabolism ; Molecular Targeted Therapy ; *Mutation ; Neurodegenerative Diseases/drug therapy/*genetics/metabolism ; Reactive Oxygen Species/metabolism

BACKGROUND: In spite of the different pathogenesis and exclusive respect in the diagnosis of Alzheimer's disease (AD) and vascular dementia (VaD), recent epidemiological and pathological studies indicates that ischemic stroke have an important role in the pathogenesis of both VaD and AD. However, the association of ischemic stroke and AD on the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insult on the regulation of amyloid precursor protein (APP) processing. METHODS: We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation, OGD) to evaluate the effect of ischemic insult on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line, SH-SY5Y, and primary cultured cells of Tg2576 APP transgenic mouse. RESULTS: Ischemic insult significantly increased the beta amyloid (A beta) production in the primary cultured cells of Tg2576 APP transgenic mice (p<0.001). A disintegrin and metalloprotease 10 (ADAM 10), a candidate of alpha-secretase, was markedly increased in the early stage of ischemic insult (up to 2 hours of OGD, p<0.001; 4 hours of OGD, p<0.05), which was followed by the decreased level of ADAM 10 expression in a later stage (p<0.001). However, the protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity were not significantly different between the group of ischemic insult and control. By contrast, the activity of gamma-secretase was significantly increased after 4 hours of ischemic insult, as compared to controls. CONCLUSIONS: This study demonstrates that the ischemic neuronal insults increase the production of A beta via activation of the amyloidogenic pathway, which may link the role of ischemic insults to the pathogenesis of AD.
Alzheimer Disease ; Amyloid Precursor Protein Secretases ; Amyloid* ; Animals ; Brain Ischemia ; Cell Line ; Cells, Cultured ; Dementia, Vascular ; Diagnosis ; Humans ; Mice ; Mice, Transgenic ; Neuroblastoma ; Neurons* ; RNA, Messenger ; Stroke

Abnormal aggregation of α-synuclein is a key element in the pathogenesis of several neurodegenerative diseases, including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-synuclein aggregation spreads through various brain regions during the course of disease progression, a propagation that is thought to be mediated by the secretion and subsequent uptake of extracellular α-synuclein aggregates between neuronal cells. Thus, aggregated forms of this protein have emerged as promising targets for disease-modifying therapy for PD and related diseases. Here, we generated and characterized conformation-specific antibodies that preferentially recognize aggregated forms of α-synuclein. These antibodies promoted phagocytosis of extracellular α-synuclein aggregates by microglial cells and interfered with cell-to-cell propagation of α-synuclein. In an α-synuclein transgenic model, passive immunization with aggregate-specific antibodies significantly ameliorated pathological phenotypes, reducing α-synuclein aggregation, gliosis, inflammation, and neuronal loss. These results suggest that conformation-specific antibodies targeting α-synuclein aggregates are promising therapeutic agents for PD and related synucleinopathies.

Progressive cognitive declines are the main clinical symptoms of Alzheimer’s disease (AD). Cognitive impairment in AD is directly correlated with amyloid beta (Aβ)-mediated synaptic deficits. It is known that upregulation of neurogranin (Ng), a postsynaptic protein, contributes to the enhancement of synaptic plasticity and cognitive function. By contrast, downregulation of Ng expression results in learning and memory impairments. Interestingly, Ng expression is significantly reduced in the parenchyma of brains with AD. However, the pathological role that downregulated Ng plays in the cognitive dysfunctions observed in AD remains unclear. Therefore, the present study examined whether enhancing Ng expression affected cognitive functions in 5XFAD mice, an animal model of AD. We found that the Ng reductions and cognitive decline observed in 5XFAD mice were restored in mice that were intrahippocampally injected with an Ng-expressing lentiviral vector. Furthermore, overexpression of Ng upregulated expression of postsynaptic density protein-95 in the hippocampus of 5XFAD mice. These results suggest that the cause of cognitive decline in AD may be at least partially associated with reduced Ng levels, and thus, supplementation of Ng may be an appropriate therapeutic strategy for individuals with AD.

Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer’s disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers.In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.

Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer’s disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers.In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.

Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer’s disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers.In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.

Numerous systemic diseases manifest with oral symptoms and signs. The molecular diagnosis of Alzheimer’s disease (AD), the most prevalent neurodegenerative disease worldwide, currently relies on invasive or expensive methods, emphasizing the imperative for easily accessible biomarkers.In this study, we explored the expression patterns of key proteins implicated in AD pathophysiology within the taste buds of mice. We detected the expression of amyloid precursor protein (APP) and tau protein in the taste buds of normal C57BL/6 mice. Phosphorylated tau was predominantly found in type II and III taste cells, while APP was located in type I taste cells. Remarkably, we observed significantly stronger immunoreactivity to phosphorylated tau in the taste buds of aged AD mouse models compared to age-matched controls. These findings underscore the oral expression of biomarkers associated with AD, highlighting the diagnostic potential of the oral cavity for neurodegenerative diseases.