Alzheimer’s disease: Advances in Genetics, Molecular and Cellular Biology Posted by R Santhosh Kalash on 9/18/2013 11:08:00 pm No comments

Roughly one hundred years ago at a meeting of Bavarian psychiatrists, Dr. Alois Alzhiemer presented the intriguing case of his patient, Auguste D., a 51 year-old female admitted to the local asylum with presenile dementia. He would argue that specific lesions in and around neurons were responsible for dementia. In the ensuing decades, studies of her disorder, which would be named Alzheimer’s disease (AD), were largely limited to descriptive neuropathological and psychological assessment of this disease with little understanding of the molecular and cellular mechanisms underlying neurodegeneration and dementia. This would change in the 1980’s when the protein components of the major neuropathological hallmarks of the disease, senile plaques (and cerebral blood vessel amyloid) and neurofibrillary tangles were first determined. The identification of the β-amyloid protein (Aβ) and the microtubule-associated tau protein as the main components of plaques and tangles, respectively, would pave the way for the molecular genetic era of AD research. By the late-1980’s, the genes encoding the β-amyloid precursor protein (APP) and tau (MAPT) were identified and would subsequently be shown to harbor autosomal dominant mutations causing early-onset familial AD and frontal temporal dementia (FTD), respectively. Later, in the early 1990’s the ε4 variant of the apoliprotein E gene (APOE) would be found to be associated with increased risk for late-onset AD. Fundamental differences were soon noted between these two AD genes: APP and APOE. First, while APP mutations caused AD with virtual certainty, the APOE-ε4 variant increased susceptibility for, but not guarantee onset of AD. Second, while APP mutations increased the generation of the neurotoxic peptide, Aβ42, in brain, APOE- ε4 affected aggregation of Aβ into fibrils and its clearance from brain. In 1995, two more familial AD genes, presenilin 1 and 2 (PSEN1, PSEN2) were identified, and mutations in MAPT were linked to frontal temporal dementia. Thus, by 1995, the stage was set for molecular studies of age-related dementias with APP, presenilin 1 and 2, APOE, and tau playing the major roles.

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