Protein Tau: Prime Cause of Synaptic and Neuronal Degeneration in Alzheimer's Disease

Abstract

The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

Early Structural and Functional Defects in Synapses and Myelinated Axons in Stratum Lacunosum Moleculare in Two Preclinical Models for Tauopathy

“…The endpoint was invariably precocious death, for Tau.P301L mice mostly between age 8–12 months (average 9 months) without survivors beyond age 12 months [29]. The age of death of biGT mice was less sharply defined, ranging from 10 to 22 months [26], [27], [46], [50], [51]. The mechanistic contributions of GSK3β in the biGT model to the delay in tauopathy and to clinical phenotype are subject of ongoing studies.…”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Mutations in the genes of presenilin 1, presenilin 2 and amyloid precursor protein are associated with the pathogenesis of the familial form of AD, suggesting that dysregulations of APP processing and Ab production are critical pathways of neurodegeneration leading to dementia in AD (Leuner et al 2007 of paired helical filaments in neuronal bodies, forming neurofibrillary tangles that become extracellular ghost tangles after the death of the neuron (Liu et al 2005). Deposition of tau protein in the brain causes loss of synaptic function and finally neuronal death (Crespo-Biel et al 2012). The number and localization of neurofibrillary tangles have been well correlated with the level of dementia, while no such correlation has been demonstrated for senile plaques (Giannakopoulos et al 2003).…”

Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair

“…Acquired, somatic mtDNA mutations have also been implicated in the process of aging and the incidence of age-related diseases [11,38–42]. Most somatic mtDNA mutations are thought to be generated by DNA replication and repair errors followed by clonal expansion of the mutated mtDNA [11,43–45]. BER is the most prominent DNA repair pathway in mitochondria.…”