Intracellular neurofibrillary tangle

The signature findings are intracellular neurofibrillary tangles (NFTs), extracellular neuritic plaques, degeneration of neurons and synapses, and cortical atrophy. 

One theory of the pathogenesis of Alzheimer s disease proposes that increased production or decreased secretion of the Ap peptides leads to accumulation of these peptides. A second theory proposes that an abnormal x-protein causes the formation of intracellular neurofibrillary tangles. x-Proteins are important in the maintenance of cytoskeleton function and axonal transport of proteins. Another theory is that Ap accumulation is a precipitating factor that is followed by the development of the x-enriched tangles in the dying neurons. 

Alzheimer s disease (AD) is neuropathologically characterized by a buildup of extracellular amyloid-(3 peptide (A(3) plaques and of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, in addition to marked... 

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). 

Alzheimer first documented the presence of extracellular senile plaques throughout the cortex and hippocampus of the AD brain and this is the most prominent pathological feature of the disease. He also described intracellular neurofibrillary tangles. The succeeding century of work has been centered on establishing the pathophysiology leading to development of these characteristic anatomic hallmarks of the disease. 

Of the 12,000 combined genes and ESTs represented on the array, only 10 changed in expression level by a factor of threefold or more, and all were upregulated. In the cortex, mRNAs for neuronal tyrosine/threonine phosphatase 1 and microtubule-associated tau were significantly enhanced. These proteins are both associated with formation/breakdown of intracellular neurofibrillary tangles, a hallmark lesion of Alzheimer s disease. Hyperphosphorylated tau has been found to be the major protein of these neurofibrillary tangles, possibly because of an imbalance in tau kinase and phosphatase activities in the affected neurons [27]. Hyperphosphorylated tau isolated from brains of patients with Alzheimer s disease has been shown to be efficiently dephosphorylated in vitro by protein phosphatases 1, 2A, and 2B. Additionally, selective inhibition of protein phosphatase 2A by okadaic acid in metabolically competent rat brain slices has been shown to induce a hyperphosphorylation and accumulation of tau like that in Alzheimer s disease [28]. Thus, upregulation of neuronal phosphatase 1 by EGb 761 could play a neuroprotective role in the brain. 

Neurofibrillary tangles are intracellular and consist of abnormally phosphorylated tau protein which is involved in microtubule assembly. Tangles interfere with neuronal function... 

Neurofibrillary tangles Intracellular knots or clumps of neurofibrils seen in the cerebral cortex in Alzheimer s disease. 

The microtubule-associated-protein tau is a component of the neurofibrillary tangles in Alzheimer s disease and a target of S100A1. PC 12 cells devoid of S100A1 were shown to be more resistant to A(3(25-35) peptide-mediated cell death and have lower levels of intracellular amyloid precursor protein (APP) (Zimmer et al., 2005). 

In AD neurons, there are three main types of neurofibrillary lesions (NFLs) according to their intracellular localization neurofibrillary tangles (NFTs) inside the cell body and apical dendrites, and neuropil threads (NThs) in distal dendrites and dysrophic neurites, associated with senile plaques. Morphologically, three major subtypes of NFTs can be distinguished, corresponding to different evolutionary stages of these lesions. 

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