期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 31, 期 1, 页码 110-118出版社
WILEY
DOI: 10.1111/j.1460-9568.2009.07031.x
关键词
beta-secretase; APP transgenic; BACE1; implicit memory; knockout
资金
- National Institute of Mental Health [R01 MH067251]
- Alzheimer's Association [IIRG-08-91231]
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH067251] Funding Source: NIH RePORTER
Although transgenic mouse models of Alzheimer's disease (AD) recapitulate amyloid-beta (A beta)-related pathologies and cognitive impairments, previous studies have mainly evaluated their hippocampus-dependent memory dysfunctions using behavioral tasks such as the water maze and fear conditioning. However, multiple memory systems become impaired in AD as the disease progresses and it is important to test whether other forms of memory are affected in AD models. This study was designed to use conditioned taste aversion (CTA) and contextual fear conditioning paradigms to compare the phenotypes of hippocampus-independent and -dependent memory functions, respectively, in 5XFAD amyloid precursor protein/presenilin-1 transgenic mice that harbor five familial AD mutations. Although both types of memory were significantly impaired in 5XFAD mice, the onset of CTA memory deficits (similar to 9 months of age) was delayed compared with that of contextual memory deficits (similar to 6 months of age). Furthermore, 5XFAD mice that were genetically engineered to have reduced levels of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) (BACE1+/-center dot 5XFAD) exhibited improved CTA memory, which was equivalent to the performance of wild-type controls. Importantly, elevated levels of cerebral beta-secretase-cleaved C-terminal fragment (C99) and A beta peptides in 5XFAD mice were significantly reduced in BACE1+/-center dot 5XFAD mice. Furthermore, A beta deposition in the insular cortex and basolateral amygdala, two brain regions that are critically involved in CTA performance, was also reduced in BACE1+/-center dot 5XFAD compared with 5XFAD mice. Our findings indicate that the CTA paradigm is useful for evaluating a hippocampus-independent form of memory defect in AD model mice, which is sensitive to rescue by partial reductions of the beta-secretase BACE1 and consequently of cerebral A beta.
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