title: Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1.
abstract: Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-beta (Abeta) accumulation and related cognitive impairments. Although deficits in hippocampus-dependent place learning have been well characterized in Alzheimer's transgenic mice, little is known about temporal memory function in these AD models. Here, we applied trace fear conditioning to two different Alzheimer's mouse models and investigated the relationship between pathogenic Abeta and temporal memory deficits. This behavioral test requires hippocampus-dependent temporal memory processing as the conditioned and unconditioned stimuli are separated by a trace interval of 30 s. We found that both amyloid precursor protein (APP) transgenic (Tg2576) and APP/presenilin (PS)1 transgenic (Tg6799) mice were impaired in memorizing this association across the time gap. Both transgenic groups performed as well as wild-type control mice in delay fear conditioning when the trace interval was removed, indicating that the trace conditioning deficits are hippocampus-specific. Importantly, Tg6799 mice engineered to lack the major Alzheimer's beta-secretase (beta-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Abeta oligomers found in Tg6799+ mouse brains returned to wild-type control levels without changes in APP/PS1 transgene expression in BACE1-/- * Tg6799+ bigenic mouse brains, suggesting Abeta oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Abeta-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Abeta oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ohno@northwestern.edu
authors.forename: Masuo
authors.initials: M
authors.lastname: Ohno
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.forename: Wilbur
authors.initials: W
authors.lastname: Tseng
authors.forename: Holly
authors.initials: H
authors.lastname: Oakley
authors.forename: Martin
authors.initials: M
authors.lastname: Citron
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.forename: John F
authors.initials: JF
authors.lastname: Disterhoft
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western / Q000379:methods; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000172:deficiency*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005239:Fear; D015151:Immunoblotting / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D008569:Memory Disorders / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse