A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer's Disease.

Tau Pathology Generated by Overexpression of Tau

Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice

Caspase-3 Is Enriched in Postsynaptic Densities and Increased in Alzheimer's Disease

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.

Zinc(Ⅱ) induced Alzheimer’s Disease (AD) prevention and suppressive progression with early, middle, and lately stages are elucidated, and subsequently zinc binding molecular mechanism on each Aβ peptide and Tau protein in progressing stages is clarified. Zinc homeostasis regulates MCI and AD prevention, in which ZnCl2 could prevent AD pathology by that zinc can reduce β-Amyloid (Aβ) and Tau proteins. Zinc transporters may allow the novel therapies that ZnT-6 functions to a likely site of Aβ generation. At AD progression with early stage, zinc-induced aggregation of Aβ peptides and tau hyperphosphorylation on amyloid and tau aggregation consider the involvement of environmental zinc in Aβ and tau pathology. Zinc can suppress spreading of the Aβ peptide and the Tau protein that elemental zinc 150 mg daily is showed to be evident for an improvement of memory, understanding, communication, and social contact in AD. Zinc induced middle stage AD progression is pathologically characterized by the deposition of Aβ plaques and hyperphosphorylated Tau Proteins (p-tau). Zinc Finger Proteins (ZNFs) regulate the accumulation of tau proteins to affect the Neurofibrillary Tangles (NFTs), resulting in the formation of NFTs, and can inhibit protein phosphatase, promoted abnormal phosphorylation of tau protein. Zinc(Ⅱ) can prevent heavy stage AD with pathological deposits of Senile Plaques (SPs) and NFTs that the tau-zinc interaction will help understanding the zinc-related tau regulation or aggregation processes in both physiological and pathological conditions. Zinc accelerates the fibrillization of human Tau and thereby increases Tau toxicity in neuronal cells with zinc exacerbated tauopathic deficits. Zinc induced toxic Reactive Oxygen Species (ROS) generation and hyperphosphorylated tau cause oxidative stress and neurotoxicity, leading to hyperphosphorylated tau damages. Zinc(Ⅱ) binding AD molecular mechanism on Aβ and Tau proteins is that Zn2+ ions which having Zn2+ ions-centered tetrahedral geometric coordination pattern and Zn-CysHis Ligands complexes with tetrahedral geometry formed, bind with Aβ and Tau proteins in each three AD progressing stages, causing Zn2+ ions-each stages protein complex formations and oxidative stress to Aβ and Tau protein cells, leading the Zn-CysHis Ligands complexes to molecular and apoptosis activities of synaptic cells.

Aβ Accelerates the Spatiotemporal Progression of Tau Pathology and Augments Tau Amyloidosis in an Alzheimer Mouse Model

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Mutations in the presenilin 1 (PS1) gene are responsible for the early onset of familial Alzheimer disease (FAD). Accumulating evidence shows that PS1 is involved in gamma-secretase activity and that FAD-associated mutations of PS1 commonly accelerate Abeta(1-42) production, which causes Alzheimer disease (AD). Recent studies suggest, however, that PS1 is involved not only in Abeta production but also in other processes that lead to neurodegeneration. To better understand the causes of neurodegeneration linked to the PS1 mutation, we analyzed the development of tau pathology, another key feature of AD, in PS1 knock-in mice. Hippocampal samples taken from FAD mutant (I213T) PS1 knock-in mice contained hyperphosphorylated tau that reacted with various phosphodependent tau antibodies and with Alz50, which recognizes the conformational change of PHF tau. Some neurons exhibited Congo red birefringence and Thioflavin T reactivity, both of which are histological criteria for neurofibrillary tangles (NFTs). Biochemical analysis of the samples revealed SDS-insoluble tau, which under electron microscopy examination, resembled tau fibrils. These results indicate that our mutant PS1 knock-in mice exhibited NFT-like tau pathology in the absence of Abeta deposition, suggesting that PS1 mutations contribute to the onset of AD not only by enhancing Abeta(1-42) production but by also accelerating the formation and accumulation of filamentous tau.

Accumulating evidence has shown the involvement of Fyn tyrosine kinase in Alzheimer’s disease (AD), in particular in the formation of neurofibrillary tangles which is one of the hallmarks of AD. Our preliminary data showed that FynT isoform directly phosphorylated tau at Tyrosine18. The data also suggested cascade of indirect phosphorylation at serine and threonine sites of tau, and accumulation of tau protein, which may lead to neurofibrillary tangle formation. Furthermore, our group previously showed that FynT expression is selectively upregulated in the AD neocortex, and is associated with neurofibrillary tangle formation and reactive astrogliosis. Hence, we hypothesize that FynT isoform may play critical roles in mediating tau pathology and neuroinflammation in neurodegenerative diseases, not exclusive to AD. Our specific aims are (1) to determine FynT and FynB isoform expression in association with tau pathology in AD and non-AD neurodegenerative dementias, and (2) to determine the role of FynT in tau pathology and neuroinflammation using transgenic mouse models. It was found that the selective upregulation of FynT but not of FynB expression in AD and LBD (Lewy Body Dementia) neocortex, was correlated with cognitive impairment, neuropathological features and neuroinflammation. Consistently, selective upregulation of FynT expression shown in our old-aged (≥ 6mo) Tau (P301S) mice overexpressing the human tau transgene, was correlated with tau pathology. Severe neuroinflammation and synaptic degeneration were also detected in these mice. Knocking out FynT in Tau mice (Double Transgenic mice) was able to reverse tau pathology, neuroinflammation and synaptic degeneration during disease progression. The male mice exhibited more severe disease pathogenesis and better disease amelioration than the females, suggesting gender differences. Our data provided strong evidence that the pathogenic FynT isoform could be a potential therapeutic target for AD and tauopathy diseases.

Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

Rac1b Increases with Progressive Tau Pathology within Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease

The pathologic hallmarks of Alzheimer's disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Progressive synaptic dysfunction and loss closely correlate with cognitive deficits in AD. Based on studies of the genes responsible for familial AD and temporal patterns of pathologic changes in AD brains, the Aβ accumulation is thought to be a primary event that influences other AD pathologies in the developmental cascade of AD. However, the details of Aβ effects on the other AD pathologies remain poorly understood. In this review, we provide an overview of the effects of Aβ in AD brains, especially focusing on synaptic dysfunction and microglia. We have recently found abnormal accumulation of a key molecule for actin assembly in NFTs of AD brains, and it was revealed that the accumulation requires not only tau pathology but also an Aβ burden in a study using transgenic mouse models of AD. Synaptic integrity is morphologically maintained by the precise regulation of actin assembly. Therefore, the results suggest the possibility that Aβ may promote NFT maturation and induce synaptic dysfunction through the disturbance of actin assembly. Thus Aβ seems to be a promoting factor in brain aging. On the other hand, we have studied microglial phagocytic ability for a compensatory pathologic reaction to Aβ accumulation. Further studies on the Aβ-dependent AD pathologies may contribute to determining novel mechanisms of AD development and new therapeutic targets in AD.

Review: 32 refs.

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease