期刊
ACTA NEUROPATHOLOGICA
卷 109, 期 1, 页码 25-31出版社
SPRINGER
DOI: 10.1007/s00401-004-0951-y
关键词
Alzheimer's disease; tauopathies; microtubule-associated protein tau; neurofibrillary degeneration; signal transduction
资金
- NATIONAL INSTITUTE ON AGING [R01AG019158] Funding Source: NIH RePORTER
- NIA NIH HHS [AG19158] Funding Source: Medline
Alzheimer's disease (AD), the major cause of dementia in middle- to old-aged individuals, is multifactorial. Independent of the etiology, whether genetic or non-genetic, this disease is characterized by extracellular beta-amyloid plaques and intraneuronal neurofibrillary tangles of abnormally hyperphosphorylated tau. However, the molecular mechanisms of neither AD nor other tauopathies are completely understood. To date, the most popular hypothesis of AD is the Amyloid cascade hypothesis, according to which beta-amyloid, the cleavage product of beta-amyloid precursor protein (APP), is neurotoxic and causes neurodegeneration and dementia. However, this hypothesis is inconsistent with the presence in normal aged human brain of the beta-amyloid plaque burden similar to that in AD, and the absence of neurofibrillary pathology and neurodegeneration in mutated APP, presenilin-1 and presenilin-2 transgenic mice that show extensive beta-amyloid plaque pathology. Here we propose an alternate hypothesis, the Metabolic/signal transduction hypothesis, which is consistent both with the pathology seen in AD and other tauopathies and as well as all experimental animal conditions. In this hypothesis, with increasing age, the fluidity of neuronal membranes is progressively reduced, which makes it less resistant to environmental/metabolic insults affecting one or more signal transduction pathways, which lead to a protein phosphorylation/dephosphorylation imbalance and abnormal hyperphosphorylation of tau. The hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, which results in breakdown of the microtubule network and, consequently, a progressive retrograde degeneration of the affected neurons and, ultimately, dementia.
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