Tau protein Hyperphosphorylation

Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2. Subsequently, other forms of frontotemporal dementia were linked to this region, resulting in the denomination frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 45-7). In 1998, mutations in tau were reported in FTDP-17 patients [29-31]. Since then, more than 30 different mutations have been described in over 80 families with FTDP-17 (Fig. 45-6). 

Rodents. Mice expressing wild-type and mutant human tau in nerve cells or glial cells have been found to develop numerous tau-immunoreactive cell bodies and processes. Abundant filaments made of hyperphosphorylated tau protein and neurodegeneration were present in some lines expressing single isoforms of mutant human tau protein [36, 37] (Fig. 45-8 and Fig. 45-9). Hyperphosphorylation of tau appeared to precede filament assembly and an... 

Protein aggregation is a common feature of all of the chronic human neurode-generative disorders. The intraneuronal inclusions in many of these diseases contain deposits of ubiquitylated proteins, indicating that perturbations of ubiquitin-dependent proteolysis may occur. The neuropathological hallmarks of AD are intraneuronal NFTs composed of hyperphosphorylated protein tau and extracellular amyloid plaques (12,23,24,191,207). Most of the ubiquitylated, hyperphosphorylated tau protein in NETs is monoubiquitylated, with the remainder polyubiquitylated, as the substrate of the 26S proteasome (258). The protein deposits in NET, neuritic plaques, and neuropil threads in the cerebral cortex of AD patients and those with... 

Alzheimer s disease (AD) along with vascular and mixed dementia is the commonest form of dementia affecting older people and accounts for 60-65% of dementia cases, whereas vascular dementia and mixed dementia account for 15-20% of the cases each (1). The Brain of individuals with AD manifest two characteristic lesions senile plaques and intracellular neurofibrillary tangles of the hyperphosphorylated tau protein (2). The amyloid fi-protein (Afi) is the principal component of the senile plaques. It is a peptide of 39-43 amino acids, derived from a larger precursor, the amyloid precursor protein (APP) (Fig. 1). 

H, Giacobini E, de Vos RA, Steur EN, Maelicke A, Albuquerque EX, Schroder H (1999) Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer s disease histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein. Eur J Neurosci 11 2551-2565... 

Another strategy to treat Alzheimer s disease, the (3-amyloid cascade theory, is based on neuropathological changes verified postmortem, the excessive appearance of which is claimed to be characteristic of the disease accumulation of neurofibrillary tangles composed of hyperphosphorylated tau proteins and extracellular senile plaques containing (3-amyloidi 4o and (3-amyloidi-42 (see Morishima-Kawashima and Iharra 2002, for review). 

The paired helical filament is made of tau protein 753 Filamentous tau is hyperphosphorylated 753... 

P Amyloid protein aggregation, leading to formation of plaques / Hyperphosphorylation of tau protein, leading to intracellular NFT development and collapse of microtubules / Inflammatory processes—levels of multiple cytokines and chemokines are elevated in AD brains / Neurovasculature dysfunction / Oxidative stress / Mitochondrial dysfunction... 

Shimura, H., Miura-Shimura, Y., Kosik, K.S. (2005) Binding of tau to heat shock protein 27 leads to decreased concentration of hyperphosphorylated tau and enhanced cell survival. J. Biol. Chem., 279, 17957-17962. 

Isolated microtubules always contain small amounts of larger 300-kDa microtubule-associated proteins (MAPS).330 These elongated molecules may in part lie in the grooves between the tubulin subunits and in part be extended outward to form a low-density layer around the tubule.283 309 Nerve cells that contain stable microtubules have associated stabilizing proteins.331 A family of proteins formed by differential splicing of mRNA are known as tau. The tau proteins are prominent components of the cytoskeleton of neurons. They not only interact with microtubules but also undergo reversible phosphorylation. Hyperphosphorylated tau is the primary component of the paired helical filaments found in the brains of persons with Alzheimer disease.330... 

Alonso AD, Zaidi T, Novak M, Barra HS, Grundke-Iqbal I, Iqbal K. Interaction of tau isoforms with Alzheimer s disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. J Biol Chem 2001 276(41) 37967-37973. 

Alzheimer s disease (AD) is one of the most common forms of dementia that affect the elderly population. The histopathological hallmarks of AD are extracellular deposits known as neuritic amyloid plaques and intraneuronal inclusions composed of hyperphosphorylated tangles enriched with tau proteins.1 The principal component of the neuritic plaques is aggregation of amyloid (A0), which is likely to play a role in the neurodegenerative process. The relative contribution of the various forms (soluble dimers, small oligomers, protofibrils, and fibrils) of A0 to neuronal... 

NFTs are the second most important pathological feature of AD. These consist of paired helical filaments that are abnormal aggregates of abnormally folded, or hyperphosphorylated, forms of the microtubule associated tau protein. The progressive increase in the distribution of NFTs throughout many regions of the brain is related to the stages in the development of the disease. Thus the NFTs first appear in the entorhinal... 

AP amyloid neuritic plaques CAA cerebral amyloid angiopathy DG Dentate gyrus DP diffuse (preamyloid) plaques NFT neurofibrillar tangles NR not reported P-Tau hyperphosphorylated MAPT tau protein. 

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