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Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1.
Eur J Neurosci 2006; 23(1):251-60EJ

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+Show Affiliations

Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ohno@northwestern.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16420434

Citation

Ohno, Masuo, et al. "Temporal Memory Deficits in Alzheimer's Mouse Models: Rescue By Genetic Deletion of BACE1." The European Journal of Neuroscience, vol. 23, no. 1, 2006, pp. 251-60.
Ohno M, Chang L, Tseng W, et al. Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci. 2006;23(1):251-60.
Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W. L., ... Disterhoft, J. F. (2006). Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. The European Journal of Neuroscience, 23(1), pp. 251-60.
Ohno M, et al. Temporal Memory Deficits in Alzheimer's Mouse Models: Rescue By Genetic Deletion of BACE1. Eur J Neurosci. 2006;23(1):251-60. PubMed PMID: 16420434.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. AU - Ohno,Masuo, AU - Chang,Lei, AU - Tseng,Wilbur, AU - Oakley,Holly, AU - Citron,Martin, AU - Klein,William L, AU - Vassar,Robert, AU - Disterhoft,John F, PY - 2006/1/20/pubmed PY - 2006/4/7/medline PY - 2006/1/20/entrez SP - 251 EP - 60 JF - The European journal of neuroscience JO - Eur. J. Neurosci. VL - 23 IS - 1 N2 - 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. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/16420434/Temporal_memory_deficits_in_Alzheimer's_mouse_models:_rescue_by_genetic_deletion_of_BACE1_ L2 - https://doi.org/10.1111/j.1460-9568.2005.04551.x DB - PRIME DP - Unbound Medicine ER -