Mechanisms of tau-induced neurodegeneration

Abstract

Alzheimer disease (AD) and related tauopathies are histopathologically characterized by a specific type of slow and progressive neurodegeneration, which involves the abnormal hyperphosphorylation of the microtubule associated protein (MAP) tau. This hallmark, called neurofibrillary degeneration, is seen as neurofibrillary tangles, neuropil threads, and dystrophic neurites and is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the non-fibrillized, abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau, which can be generated by catalysis of several different combinations of protein kinases, also promotes its misfolding, decrease in turnover, and self-assembly into tangles of paired helical and or straight filaments. Some of the abnormally hyperphosphorylated tau ends up both amino and C-terminally truncated. Disruption of microtubules by the non-fibrillized abnormally hyperphosphorylated tau as well as its aggregation as neurofibrillary tangles probably impair axoplasmic flow and lead to slow progressive retrograde degeneration and loss of connectivity of the affected neurons. Among the phosphatases, which regulate the phosphorylation of tau, protein phosphatase-2A (PP2A), the activity of which is down-regulated in AD brain, is by far the major enzyme. The two inhibitors of PP-2A, I1PP2A and I2PP2A, which are overexpressed in AD, might be responsible for the decreased phosphatase activity. AD is multifactorial and heterogeneous and involves more than one etiopathogenic mechanism.

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

“…14 The presence of aggregates of TAU, an RdCVFL interacting protein indicates that the death of photoreceptors in the Nxnl1À/À retina may be triggered by these aggregates, as reported in Alzheimer's disease. 25 TUNEL-positive cells are not detected, however, this may be explained by the slower rate of degeneration observed here, with 20% of the cells in the ONL lost over a period of 6 months as compared with the rd1, which looses 97% of these cells over 15 days (Supplementary Figure S2). The reduced cone number and function (Figures 2a-d, 3a-b) is evidence that RdCVF is involved in the viability of these photoreceptors.…”

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

“…The size of the neuronal soma pales in comparison with the area covered by axons and dendrites, and consequently, elevated Aβ 1-42 levels in the central nervous system will most frequently first be encountered by neurites, and pathogenic signaling mechanisms will initially be triggered within axons and dendrites. Indeed, many pathogenic alterations in AD, including tau hyperphosphorylation and synaptic changes, occur first in axons or dendrites, respectively [47,48]. However, the pathogenic changes elicited by locally sensed Aβ are not restricted to neurites but are propagated retrogradely to the neuronal soma.…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…From the histopathologic point of view, neurofibrillary tangles (aggregates of cytoskeletal hyperphosphorylated tau protein), extracellular amyloid plaques [formed by the pathologic proteolytic processing of amyloid β precursor protein (APP)], and massive neuronal death are observed in several brain regions (cortex, hippocampus, and amygdala) [144,145]. One distinctive hallmark of AD is the progressive and irreversible loss of cholinergic neurons in the basal forebrain [146].…”