Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention

Abstract

• Introduction • Significance • Etiopathogenesis • Mechanism by which ab normal hyperphosphorylation of tau leads to neurofibrillary degeneration • Signal transduction pathways involved ‐ Tau kinases ‐ Tau phosphatases ‐ PP‐2A inhibitors ‐ Involvement of more than one kinase ‐ Phosphorylation site in abnormal hyperphosphorylation of tau • Role of decreased brain glucose metabolism in neurofibrillary degeneration • Subgroups of AD • Therapeutic approaches to inhibit neurofibrillary degeneration Abstract Alzheimer disease (AD) is multi‐factorial and heterogeneous. Independent of the aetiology, this disease is characterized clinically by chronic and progressive dementia and histopathologically by neurofibrillary degeneration of abnormally hyperphosphorylated tau seen as intraneuronal neurofibrillary tangles, neuropil threads and dystrophic neurites, and by neuritic (senile) plaques of β‐amyloid. The neurofibrillary degeneration is apparently required for the clinical expression of AD, and in related tauopathies it leads to dementia in the absence of amyloid plaques. While normal tau promotes assembly and stabilizes microtubules, the abnormally hyperphosphorylated tau sequesters normal tau, MAP1 and MAP2, and disrupts microtubules. The abnormal hyperphosphorylation of tau also promotes its self‐assembly into tangles of paired helical and or straight filaments. Tau is phosphorylated by a number of protein kinases. Glycogen synthase kinase‐3 (GSK‐3) and cyclin dependent protein kinase 5 (cdk5) are among the kinases most implicated in the abnormal hyperphosphorylation of tau. Among the phosphatases which regulate the phosphorylation of tau, protein phosphatase‐2A (PP‐2A), the activity of which is down‐regulated in AD brain, is by far the major enzyme. The inhibition of abnormal hyperphosphorylation of tau is one of the most promising therapeutic targets for the development of disease modifying drugs. A great advantage of inhibiting neurofibrillary degeneration is that it can be monitored by evaluating the levels of total tau and tau phosphorylated at various known abnormally hyperphosphorylated sites in the cerebrospinal fluid of patients, obtained by lumbar puncture. There are at least five subgroups of AD, each is probably caused by a different etiopathogenic mechanism. The AD subgroup identification of patients can help increase the success of clinical trials and the development of specific and potent disease modifying drugs.