Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain.
The hypothesis that amyloid-beta (Abeta) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. Abeta peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICD-overexpressing transgenic mice that showed abnormal activation of GSK-3beta, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3beta inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of Abeta have important therapeutic implications and may explain some observations that are discordant with the amyloid hypothesis.
Ghosal
Kaushik
K
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Vogt
Daniel L
DL
Liang
Man
M
Shen
Yong
Y
Lamb
Bruce T
BT
Pimplikar
Sanjay W
SW
D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D018020:Lithium Compounds / Q000627:therapeutic use; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D018020:Lithium Compounds; D016875:tau Proteins