期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：16
页码：9572-9577
DOI：10.1073/pnas.1133381100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-{beta} peptides (A{beta}) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of A{beta}1-42 but not with the amount of A{beta} deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between A{beta}-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.
