Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 167, Issue 5, Pages 1361-1369Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)61223-0
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Funding
- NIA NIH HHS [AG-11542, P01 AG017628, P01 AG011542, AG-14382, P01 AG014382, AG-17628] Funding Source: Medline
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]Impaired rapid eye movement sleep (REMS) is commonly, observed in Alzheimer's disease, suggesting injury to mesopontine cholinergic neurons. We sought to determine whether abnormal beta-amyloid peptides impair REMS and injure mesopontine cholinergic neurons in transgenic (hAPP695.SWE) mice (Tg2576) that model brain amyloid pathologies. Tg2576 mice and wild-type littermates were studied at 2, 6, and 12 months by using sleep recordings, contextual fear conditioning, and immunohistochemistry. At 2 months of age, REMS was indistinguishable by genotype but was reduced in Tg2576 mice at 6 and 12 months. Choline acetyltransferase-positive neurons in the pedunculopontine tegmentum of Tg2576 mice at 2 months evidenced activated caspase-3 immunoreactivity, and at 6 and 12 months the numbers of pedunculopontine tegmentum choline acetyltransferase-positive neurons were reduced in the Tg2576 mice. Other cholinergic groups involved in REMS were unperturbed. At 12 months, Tg2576 mice demonstrated increased 3-nitrotyrosine immunoreactivity in cholinergic projection sites but not in cholinergic soma. We have identified a population of selectively compromised cholinergic neurons in young Tg2576 mice that manifest early onset REMS impairment. The differential vulnerability of these cholinergic neurons to A beta injury provides an invaluable tool with which to understand mechanisms of sleep/wake perturbations in Alzheimer's disease.
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