Intraneuronal A beta 42 accumulation in human brain

Alzheimer's disease (AD) is characterized by the deposition of senile plaqu es (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SP s are composed of aggregated beta-amyloid (A beta) 40/42(43) peptides, Evid ence implicates a central role for A beta in the pathophysiology of AD. Mut ations in beta APP and presenilin 1 (PS1) lead to elevated secretion of A b eta, especially the more amyloidogenic A beta 42. Immunohistochemical studi es have also emphasized the importance of A beta 42 in initiating plaque pa thology. Cell biological studies have demonstrated that A beta is generated intracellularly. Recently, endogenous A beta 42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and withi n neurons of PS1 mutant transgenic mice. A central question about the role of A beta in disease concerns whether extracellular A beta deposition or in tracellular A beta accumulation initiates the disease process. Here we repo rt that human neurons in AD-vulnerable brain regions specifically accumulat e gamma-cleaved A beta 42 and suggest that this intraneuronal A beta 42 imm unoreactivity appears to precede both NFT and A beta plaque deposition. Thi s study suggests that intracellular A beta 42 accumulation is an early even t in neuronal dysfunction and that preventing intraneuronal A beta 42 aggre gation may be an important therapeutic direction for the treatment of AD.