Neurosteroids and sporadic Alzheimer s diseas.

Abstract:  A reduction of neurosteroids in the brain may initiate sporadic Alzheimer's disease (AD) which comprises >99% of all AD cases. AD research is currently focused on aberrant amyloid precursor protein (APP) processing and the hyper-phosphorylatio n of tau protein. This is based on early-onset genetic and pathological observations clearly showing that these markers are involved in the progression of the disease. However, there is still ongoing debate as to the key pathological events in the sporadic form of AD where the Abeta and tau genes are not usually mutated. The vulnerability of the transentorhinal cortex, which displays the first architectural signs of AD, may be related to its role as the entry point for an enormous amount of excitatory information, the majority from the neocortex, which passes through the hippocampal formation. Neurosteroids provide a layer of protection from excessive excitation, and their age-related decrease may expose the vulnerability required to allow neuronal death by excitotoxicity and thereby initiate the disease.