Intraneuronal beta-amyloid expression downregulates the Akt survival pathway and blunts the stress response.
Early events in Alzheimer's disease (AD) pathogenesis implicate the accumulation of beta-amyloid (Abeta) peptide inside neurons in vulnerable brain regions. However, little is known about the consequences of intraneuronal Abeta on signaling mechanisms. Here, we demonstrate, using an inducible viral vector system to drive intracellular expression of Abeta42 peptide in primary neuronal cultures, that this accumulation results in the inhibition of the Akt survival signaling pathway. Induction of intraneuronal Abeta42 expression leads to a sequential decrease in levels of phospho-Akt, increase in activation of glycogen synthase kinase-3beta, and apoptosis. Downregulation of Akt also paralleled intracellular Abeta accumulation in vivo in the Tg2576 AD mouse model. Overexpression of constitutively active Akt reversed the toxic effects of Abeta 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 Abeta accumulation in AD involve the associated impairments of Akt signaling and suppression of the stress response.
Magrané
Jordi
J
Department of Neurology, Caritas Saint Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02135, USA.
Rosen
Kenneth M
KM
Smith
Roy C
RC
Walsh
Kenneth
K
Gouras
Gunnar K
GK
Querfurth
Henry W
HW
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000506:poisoning; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015536:Down-Regulation; D045604:Extracellular Fluid / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology*; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051057:Proto-Oncogene Proteins c-akt