Altered Tau and Neurofilament Proteins in Neuro‐Degenerative Diseases: Diagnostic Implications for Alzheimer's Disease and Lewy Body Dementias

Abstract

The neuronal cytoskeleton is one of the most profoundly altered organelles in late life neuro-degenerative disorders that are characterized by progressive impairments in cognitive abilities. The elucidation of the protein building blocks of these organelles as well as advances in understanding how these proteins become altered in Alzheimer's disease (AD) and other less common dementing illnesses, i.e., diffuse Lewy body disease (DLBD) or the Lewy body variant of AD (LBVAD), will provide insights into the molecular basis of these disorders. Within, we review evidence that normal adult human tau is abnormally phosphorylated and converted into the subunits of AD paired helical filaments (PHFs), and that Lewy bodies (LBs) represent accumulation of altered neurofilament (NF) triplet subunits. Although the precise biological consequences of PHF and LB formation in neurons is unknown, growing evidence suggests that the formation of PHFs and LBs from normal neuronal cytoskeletal proteins could have deleterious effects on neuronal function and survival. Finally, insights into the composition of PHFs and LBs could lead to the development of novel strategies for the timely and accurate diagnosis of AD, DLBD and the LBVAD.

Intracellular domains of amyloid precursor-like protein 2 interact with CP2 transcription factor in the nucleus and induce glycogen synthase kinase-3β expression

“…39 Hyperphosphorylated t forms NFTs, one of the hallmarks of AD, and leads to apoptosis by disrupting cytoskeletal and axonal transport. 40 GSK-3b has been identified as a primary kinase in this process among several protein kinases including cdc2, cdk5 and MAP kinases. 23 The changes in the levels of phosphorylated t were examined by using AT8 antibody, which recognizes phosphorylated t at its Ser 202 and Thr 205 sites.…”

An extensive network of PHFτ‐rich dystrophic neurites permeates neocortex and nearly all neuritic and diffuse amyloid plaques in Alzheimer disease

“…The diagnosis of AD was based on consensus criteria [19] as described [7,11,12]. None of the AD cases had cortical Lewy bodies [14,20]. Five cortical areas were studied, i.e.…”

“…the neuritic and diffuse plaque, differ with respect to composition and structure [7,&l 1,12,14]. For example, aberrantly phosphorylated r proteins (A68 or PHFz) that form paired helical tilaments (PHFs) in neurofibrillary tangles (NFTs) have been found in dystrophic processes associated with neuritic plaques (NPs), but a number of studies have failed to detect PHFr in diffuse plaques [14]. Since this might signify that diffuse and neuritic plaques arise from different mechanisms, we re-examined this issue by conventional and confocal microscopy using double label immunohistochemistry.…”

Tau Released from Paired Helical Filaments with Formic Acid or Guanidine Is Susceptible to Calpain‐Mediated Proteolysis

“…Abnormal, fibrillary forms of tau proteins known as paired helical filaments (PHFs), accumulate in the brains of individuals affected with AD (Kidd, 1963;Grundke-Iqbal et al, 1986) and certain other neurodegenerative disorders (Trojanowski et al, 1993), including corticobasal degeneration (Feany et al, 1995), progressive supranuclear palsy (Flament et al, 1991), and Pick's disease (Murayama et al, 1990;Delacourte et al, 1996). The pathologic accumulation of PHFs could be the result of impairments in proteolytic degradation pathways in these various neurodegenerative disorders.…”