Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 156, Issue 1, Pages 15-20Publisher
AMER SOC INVESTIGATIVE PATHOLOGY, INC
DOI: 10.1016/S0002-9440(10)64700-1
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Funding
- NIA NIH HHS [P01 AG009464, P50 AG005138, AG05138, AG09464] Funding Source: Medline
- NINDS NIH HHS [NS02037] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [K08NS002037] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG009464, P50AG005138] Funding Source: NIH RePORTER
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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.
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