Intraneuronal Aβ42 accumulation in human brain

Alzheimer's disease (AD) is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are composed of aggregated beta-amyloid (A beta) 40/42(43) peptides, Evidence implicates a central role for A beta in the pathophysiology of AD. Mutations in beta APP and presenilin 1 (PS1) lead to elevated secretion of A beta, especially the more amyloidogenic A beta 42. Immunohistochemical studies have also emphasized the importance of A beta 42 in initiating plaque pathology. 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 within neurons of PS1 mutant transgenic mice. A central question about the role of A beta in disease concerns whether extracellular A beta deposition or intracellular A beta accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate gamma-cleaved A beta 42 and suggest that this intraneuronal A beta 42 immunoreactivity appears to precede both NFT and A beta plaque deposition. This study suggests that intracellular A beta 42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal A beta 42 aggregation may be an important therapeutic direction for the treatment of AD.