Alzheimer Neurofibrillary Degeneration: Pivotal Role and Therapeutic Targets
Neurofibrillary degeneration of abnormally hyperphosphorylated tau is seen as intraneuronal neurofibrillary tangles, neuropil threads and dystrophic neurites surrounding β-amyloid plaques. The neurofibrillary degeneration is apparently required for the clinical expression of Alzheimer disease (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, among others, by glycogen synthase kinase-3 (GSK-3) and cyclin dependent protein kinase 5 (cdk5), and dephosphorylated by protein phosphatase-2A (PP-2A), the activity of which is down-regulated in AD brain. Phosphorylation of tau is also regulated by its O-GlcNAcylation, which in turn is affected by brain glucose metabolism. The inhibition of abnormal hyperphosphorylation of tau, which is a multi-targets target is one of the most promising therapeutic approaches 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.