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Intraneuronal Aβ42 accumulation in human brain

Gouras, Gunnar K. LU orcid ; Tsai, Julia ; Naslund, Jan ; Vincent, Bruno ; Edgar, Mark ; Checler, Frederic ; Greenfield, Jeffrey P. ; Haroutunian, Vahram ; Buxbaum, Joseph D. and Xu, Huaxi , et al. (2000) In American Journal of Pathology 156(1). p.15-20
Abstract

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 β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and within neurons of PS1 mutant transgenic... (More)

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 β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 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 Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunore-activity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD.

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publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Pathology
volume
156
issue
1
pages
15 - 20
publisher
American Society for Investigative Pathology
external identifiers
  • scopus:0033622324
  • pmid:10623648
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)64700-1
language
English
LU publication?
no
id
2a969fd9-6e7a-43a0-9352-b5e836e615af
date added to LUP
2020-02-20 14:27:55
date last changed
2025-06-26 22:41:44
@article{2a969fd9-6e7a-43a0-9352-b5e836e615af,
  abstract     = {{<p>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 β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 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 Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunore-activity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD.</p>}},
  author       = {{Gouras, Gunnar K. and Tsai, Julia and Naslund, Jan and Vincent, Bruno and Edgar, Mark and Checler, Frederic and Greenfield, Jeffrey P. and Haroutunian, Vahram and Buxbaum, Joseph D. and Xu, Huaxi and Greengard, Paul and Relkin, Norman R.}},
  issn         = {{0002-9440}},
  language     = {{eng}},
  month        = {{01}},
  number       = {{1}},
  pages        = {{15--20}},
  publisher    = {{American Society for Investigative Pathology}},
  series       = {{American Journal of Pathology}},
  title        = {{Intraneuronal Aβ42 accumulation in human brain}},
  url          = {{http://dx.doi.org/10.1016/S0002-9440(10)64700-1}},
  doi          = {{10.1016/S0002-9440(10)64700-1}},
  volume       = {{156}},
  year         = {{2000}},
}