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Animal Models |
¶
From the Department of Medicine,*
Division ofGeriatric Medicine, the Departments of BiologicalChemistry,
Pathology,
and Neurology,
the Institute ofGerontology,¶
the Department ofRadiology,||
Division of Nuclear Medicine, and theNeuroscience Program,**
University of Michigan,Ann Arbor, Michigan; the Veterans Affairs Medical Center GeriatricsResearch Education and ClinicalCenter,
Ann Arbor, Michigan;and the Department of Preventive Medicine andBiometrics,
Division of Epidemiology andBiostatistics, Uniformed Services University of the Health Sciences,Bethesda, Maryland
Abstract
We examined presynaptic cholinergic markers and ß-secretase activity during progressive central nervous system amyloidogenesis in Tg2576 Alzheimer mice (transgenic for human amyloid precursor protein Swedish mutation; hAPPswe). At 14, 18, and 23 months of age there were no significant differences between wild-type and transgenic mice in four distinct central nervous system cholinergic indices—choline acetyltransferase and acetylcholinesterase activities, and binding to vesicular acetylcholine transporter and Na+-dependent high-affinity choline uptake sites. A novel enzyme-linked immunosorbent assay measuring only the secreted human ß-secretase cleavage product (APPsßswe) of APPswe also revealed no change with aging in Tg2576 mouse brain. In contrast, transgenic but not wild-type mice exhibited an age-dependent increase in soluble Aß40 and Aß42 levels and progressive amyloid deposition in brain. Thus, aging Tg2576 mice exhibited presynaptic cholinergic integrity despite progressively increased soluble Aß40 and Aß42 levels and amyloid plaque density in brain. Older Tg2576 mice may best resemble preclinical or early stages of human Alzheimer’s disease with preserved presynaptic cholinergic innervation. Homeostatic APPsßswe levels with aging suggest that progressive amyloid deposition in brain results not from increased ß-secretase cleavage of APP but from impaired Aß/amyloid clearance mechanisms.
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