Memory Deficits Correlating with Acetylcholinesterase Splice Shift and Amyloid Burden in Doubly Transgenic Mice

Authors: Rees, Tina M.; Berson, Amit; Sklan, Ella H.; Younkin, Linda; Younkin, Steven; Brimijoin, Stephen; Soreq, Hermona

Source: Current Alzheimer Research, Volume 2, Number 3, July 2005 , pp. 291-300(10)

Publisher: Bentham Science Publishers

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Abstract:

Current mouse models of Alzheimer's disease show brain pathology that correlates to a degree with memory impairment, but underlying molecular mechanisms remained unknown. Here we report studies with three lines of transgenic mice: animals that doubly express mutated human amyloid precursor protein (APPswe) and human acetylcholinesterase (hAChE); and animals transgenic for only the APPswe or the hAChE. Among these genotypes, variations were observed in expression of mRNA for presenilin-1, which was highest in singly transgenic hAChE mice, and the stressinducible form of AChE, which was elevated when both transgenes were present. At the age of nine months, both double and single transgenic mice displayed working memory impairment in a radial arm water maze. However, as compared with mice expressing amyloid alone, the double transgenic animals exhibited more numerous plaques and greater amyloid burden in brain (both by histochemistry and by ELISA of amyloid protein). Moreover, the amyloid burden in double transgenics was tightly correlated with memory impairment as measured by total maze errors (r2 = 0.78, p = .002). This correlation was markedly stronger than observed in mice with amyloid alone. These new findings support the notion of cholinergic-amyloid interrelationships and highlight the double transgenic mice as a promising alternative for testing Alzheimer's therapies.

Keywords: alzheimers disease; acetylcholinesterase variants; amyloid precursor protein; cerebral cortex; hippocampus; presenilin

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1567205054367847

Affiliations: 1: Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.

Publication date: 2005-07-01

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Current Alzheimer Research publishes peer-reviewed frontier review and research articles on all areas of Alzheimer's disease. This multidisciplinary journal will help in understanding the neurobiology, genetics, pathogenesis, and treatment strategies of Alzheimer's disease. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, molecular, and animal models. The journal also covers original articles on recent research in fast emerging areas of molecular diagnostics, brain imaging, drug development and discovery, and clinical aspects of Alzheimer's disease. Manuscripts are encouraged that relate to the synergistic mechanism of Alzheimer's disease with other dementia and neurodegenerative disorders. Book reviews, meeting reports and letters-to-the-editor are also published. The journal is essential reading for researchers, educators and physicians with interest in age-related dementia and Alzheimer's disease. Current Alzheimer Research provides a comprehensive 'bird's-eye view' of the current state of Alzheimer's research for neuroscientists, clinicians, health science planners, granting, caregivers and families of this devastating disease.

Memory Deficits Correlating with Acetylcholinesterase Splice Shift and Amyloid Burden in Doubly Transgenic Mice

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