Pathological Features of AD

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... 

Neurodegeneration is an important but not a unique characteristic feature of AD. What distinguishes AD from other neurodegenerative diseases is the presence of its telltale pathologies in the brains of these patients amyloid plaques and neurofibrillary tangles (NFTs). Amyloid plaques consist of mainly extracellular /f-amyloid (A/i) peptide while neurofibrillary tangles are... 

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. 

AD is characterized by marked atrophy of the cerebral cortex and loss of cortical and subcortical neurons. The pathological hallmarks of AD are senile plaques, which are spherical accumulations of the protein -amyloid accompanied by degenerating neuronal processes, and abundant neurofibrillary tangles, composed of paired helical filaments and other proteins. In advanced AD, senile plaques and neurofibrillary tangles are most abundant in the hippocampus and associative regions of the cortex, whereas areas such as the visual and motor cortices are relatively spared. This corresponds to the clinical features of marked impairment of memory and abstract reasoning, with preservation of vision and movement. 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

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