Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice.
We examined presynaptic cholinergic markers and beta-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 beta-secretase cleavage product (APPsbetaswe) 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 Abeta40 and Abeta42 levels and progressive amyloid deposition in brain. Thus, aging Tg2576 mice exhibited presynaptic cholinergic integrity despite progressively increased soluble Abeta40 and Abeta42 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 APPsbetaswe levels with aging suggest that progressive amyloid deposition in brain results not from increased beta-secretase cleavage of APP but from impaired Abeta/amyloid clearance mechanisms.
Gau
Jen-Tzer
JT
Department of Medicine, Division of Geriatric Medicine, the Institute of Gerontology, University of Michigan, Ann Arbor, MI 48105, USA.
Steinhilb
Michelle L
ML
Kao
Tzu-Cheg
TC
D'Amato
Constance J
CJ
Gaut
James R
JR
Frey
Kirk A
KA
Turner
R Scott
RS
D000110:Acetylcholinesterase / Q000378:metabolism*; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D015415:Biomarkers; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009467:Neuromuscular Depolarizing Agents / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D009467:Neuromuscular Depolarizing Agents; D010880:Piperidines; C006189:vesamicol; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse