Tau-induced neurodegeneration: mechanisms and targets

Abstract

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

“…Tau pathology has a devastating effect on synaptic function (Gomez-Isla et al, 1997;Beharry et al, 2014;Spires-Jones and Hyman, 2014) and relates more strongly to cognitive functions during life than does amyloid-b (Arriagada et al, 1992;Nelson et al, 2012;van Rossum et al, 2012;Rolstad et al, 2013). However, current knowledge about relationships between tau pathology and other disease measures is mainly derived from animal, neuropathological and CSF studies.…”

NMR Spectroscopic Studies of the Conformational Ensembles of Intrinsically Disordered Proteins

“…Additionally, many IDPs are hyperphosphorylated. For example, hyperphosphorylation of the neuronal protein tau abolishes its interaction with microtubules and promotes the formation of pathogenic paired helical fragments (Beharry et al 2014); hyperphosphorylation of the secreted osteopontin is required for its interaction with Ca 2+ and CD44 (Hunter 2013;Kazanecki et al 2007) (Fig. 5.11).…”

Overexpression of Tau Rescues Nogo-66-Induced Neurite Outgrowth Inhibition In Vitro

“…Tau also regulates the dynamic instability of microtubules involved in reorganization of the cytoskeleton [8,9]. In recent years, studies have focused on the pathological role of tau in the neurodegenerative diseases known as tauopathies [10][11][12], including Alzheimer's disease, Parkinson's disease, corticobasal degeneration, argyrophilic grain disease, Pick's disease, and Huntington's disease.…”