Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice.
Accumulation of beta-amyloid (Abeta) peptides in the cerebral cortex is considered a key event in the pathogenesis of Alzheimer's disease (AD). Presenilin 1 (PS1) plays an essential role in the gamma-secretase cleavage of the amyloid precursor protein (APP) and the generation of Abeta peptides. Reduction of Abeta generation via the inhibition of gamma-secretase activity, therefore, has been proposed as a therapeutic approach for AD. In this study, we examined whether genetic inactivation of PS1 in postnatal forebrain-restricted conditional knock-out (PS1 cKO) mice can prevent the accumulation of Abeta peptides and ameliorate cognitive deficits exhibited by an amyloid mouse model that overexpresses human mutant APP. We found that conditional inactivation of PS1 in APP transgenic mice (PS1 cKO;APP Tg) effectively prevented the accumulation of Abeta peptides and formation of amyloid plaques and inflammatory responses, although it also caused an age-related accumulation of C-terminal fragments of APP. Short-term PS1 inactivation in young PS1 cKO;APP Tg mice rescued deficits in contextual fear conditioning and serial spatial reversal learning in a water maze, which were associated with APP Tg mice. Longer-term PS1 inactivation in older PS1 cKO;APP Tg mice, however, failed to rescue the contextual memory and hippocampal synaptic deficits and had a decreasing ameliorative effect on the spatial memory impairment. These results reveal that in vivo reduction of Abeta via the inactivation of PS1 effectively prevents amyloid-associated neuropathological changes and can, but only temporarily, improve cognitive impairments in APP transgenic mice.
Saura
Carlos A
CA
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chen
Guiquan
G
Malkani
Seema
S
Choi
Se-Young
SY
Takahashi
Reisuke H
RH
Zhang
Dawei
D
Gouras
Gunnar K
GK
Kirkwood
Alfredo
A
Morris
Richard G M
RG
Shen
Jie
J
D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001522:Behavior, Animal / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology; D053764:Presenilin-1; D017729:Presynaptic Terminals / Q000378:metabolism; D013028:Space Perception / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse