Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 50, Pages 11693-11709Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2766-05.2005
Keywords
BACE1 null mice; selective vulnerability; A beta amyloidosis; Alzheimer's; cognition; synaptic plasticity; RNAi
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Funding
- Intramural NIH HHS [Z01 AG000959-04, Z99 AG999999] Funding Source: Medline
- NIA NIH HHS [P50 AG05146, AG02556, P50 AG005146] Funding Source: Medline
- NINDS NIH HHS [R01 NS45150, R01 NS041438, P01 NS047308, R01 NS41438, R01 NS045150] Funding Source: Medline
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A transmembrane aspartyl protease termed beta-site APP cleavage enzyme 1 (BACE1) that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons, is required for the generation of amyloid-beta(A beta) peptides implicated in the pathogenesis of Alzheimer's disease (AD). We now demonstrate that BACE1, enriched in neurons of the CNS, is a major determinant that predisposes the brain to A beta amyloidogenesis. The physiologically high levels of BACE1 activity coupled with low levels of BACE2 and alpha-secretase anti-amyloidogenic activities in neurons is a major contributor to the accumulation of A beta in the CNS, whereas other organs are spared. Significantly, deletion of BACE1 in APPswe;PS1 Delta E9 mice prevents both A beta deposition and age-associated cognitive abnormalities that occur in this model of A beta amyloidosis. Moreover, A beta deposits are sensitive to BACE1 dosage and can be efficiently cleared from the CNS when BACE1 is silenced. However, BACE1 null mice manifest alterations in hippocampal synaptic plasticity as well as in performance on tests of cognition and emotion. Importantly, memory deficits but not emotional alterations in BACE1(-/-) mice are prevented by coexpressing APPswe;PS1 Delta E9 transgenes, indicating that other potential substrates of BACE1 may affect neural circuits related to emotion. Our results establish BACE1 and APP processing pathways as critical for cognitive, emotional, and synaptic functions, and future studies should be alert to potential mechanism-based side effects that may occur with BACE1 inhibitors designed to ameliorate A beta amyloidosis in AD.
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