Intraneuronal β-amyloid expression downregulates the Akt survival pathway and blunts the stress response
Magrané, Jordi ; Rosen, Kenneth M. ; Smith, Roy C. ; Walsh, Kenneth ; Gouras, Gunnar K. LU
and Querfurth, Henry W.
(2005)
In The Journal of Neuroscience
25(47).
p.10960-10969
- Abstract
Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of β-amyloid (Aβ) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Aβ on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Aβ42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Aβ42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3β, and apoptosis. Downregulation of Akt also paralleled intracellular Aβ accumulation in vivo in the Tg2576 AD mouse... (More)
Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of β-amyloid (Aβ) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Aβ on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Aβ42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Aβ42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3β, and apoptosis. Downregulation of Akt also paralleled intracellular Aβ accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of Aβ through a mechanism involving the induction of heat shock proteins (Hsps). We used a small-interfering RNA approach to explore the possibility of a link between Akt activity and Hsp70 expression and concluded that neuroprotection by Akt could be mediated through downstream induction of Hsp70 expression. These results suggest that the early dysfunction associated with intraneuronal Aβ accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response.
(Less)
- author
- Magrané, Jordi
; Rosen, Kenneth M.
; Smith, Roy C.
; Walsh, Kenneth
; Gouras, Gunnar K.
LU
and Querfurth, Henry W.
- publishing date
- 2005-11-23
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Akt, Alzheimer, Amyloid, Hsp, Intracellular, Stress response
- in
- The Journal of Neuroscience
- volume
- 25
- issue
- 47
- pages
- 10960 - 10969
- publisher
- Society for Neuroscience
- external identifiers
-
- scopus:28044446528
- pmid:16306409
- ISSN
- 0270-6474
- DOI
- 10.1523/JNEUROSCI.1723-05.2005
- language
- English
- LU publication?
- no
- id
- 03cfdb04-2aff-484e-a704-59aa7814a9de
- date added to LUP
- 2020-02-20 14:30:15
- date last changed
- 2024-05-01 06:29:25
@article{03cfdb04-2aff-484e-a704-59aa7814a9de,
abstract = {{<p>Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of β-amyloid (Aβ) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Aβ on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Aβ42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Aβ42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3β, and apoptosis. Downregulation of Akt also paralleled intracellular Aβ accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of Aβ through a mechanism involving the induction of heat shock proteins (Hsps). We used a small-interfering RNA approach to explore the possibility of a link between Akt activity and Hsp70 expression and concluded that neuroprotection by Akt could be mediated through downstream induction of Hsp70 expression. These results suggest that the early dysfunction associated with intraneuronal Aβ accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response.</p>}},
author = {{Magrané, Jordi and Rosen, Kenneth M. and Smith, Roy C. and Walsh, Kenneth and Gouras, Gunnar K. and Querfurth, Henry W.}},
issn = {{0270-6474}},
keywords = {{Akt; Alzheimer; Amyloid; Hsp; Intracellular; Stress response}},
language = {{eng}},
month = {{11}},
number = {{47}},
pages = {{10960--10969}},
publisher = {{Society for Neuroscience}},
series = {{The Journal of Neuroscience}},
title = {{Intraneuronal β-amyloid expression downregulates the Akt survival pathway and blunts the stress response}},
url = {{http://dx.doi.org/10.1523/JNEUROSCI.1723-05.2005}},
doi = {{10.1523/JNEUROSCI.1723-05.2005}},
volume = {{25}},
year = {{2005}},
}