Intraneuronal Abeta42 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 (Abeta) 40/42(43) peptides. Evidence implicates a central role for Abeta in the pathophysiology of AD. Mutations in betaAPP and presenilin 1 (PS1) lead to elevated secretion of Abeta, especially the more amyloidogenic Abeta42. Immunohistochemical studies have also emphasized the importance of Abeta42 in initiating plaque pathology. Cell biological studies have demonstrated that Abeta is generated intracellularly. Recently, endogenous Abeta42 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 Abeta in disease concerns whether extracellular Abeta deposition or intracellular Abeta accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate gamma-cleaved Abeta42 and suggest that this intraneuronal Abeta42 immunoreactivity appears to precede both NFT and Abeta plaque deposition. This study suggests that intracellular Abeta42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Abeta42 aggregation may be an important therapeutic direction for the treatment of AD.
Gouras
G K
GK
Laboratory of Molecular and Cellular Neuroscience and Fisher Center for Research on Alzheimer's Disease, The Rockefeller University New York, New York 10021, USA. gkgouras@mail.med.cornell.edu
Tsai
J
J
Naslund
J
J
Vincent
B
B
Edgar
M
M
Checler
F
F
Greenfield
J P
JP
Haroutunian
V
V
Buxbaum
J D
JD
Xu
H
H
Greengard
P
P
Relkin
N R
NR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002102:Cadaver; D003072:Cognition Disorders / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000473:pathology; D012016:Reference Values
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)