Temporal memory deficits in Alzheimer's mouse models: Rescue by genetic deletion of BACE1

Masuo Ohno*, Lei Chang, Wilbur Tseng, Holly Oakley, Martin Citron, William L. Klein, Robert Vassar, John F. Disterhoft

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

250 Scopus citations


Transgenic mouse models of Alzheimer's disease (AD) exhibit amyloid-β (Aβ) 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 Aβ 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 β-secretase (β-site APP-cleaving enzyme 1: BACE1) showed behavioral rescue from temporal memory deficits. Elevated levels of soluble Aβ 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 Aβ oligomers as potential mediators of memory loss. Thus, trace fear conditioning is a useful assay to test the mechanisms and therapeutic interventions for Aβ-dependent deficits in temporal associative memory. Our gene-based approach suggests that lowering soluble Aβ oligomers by inhibiting BACE1 may be beneficial for alleviating cognitive disorders in AD.

Original languageEnglish (US)
Pages (from-to)251-260
Number of pages10
JournalEuropean Journal of Neuroscience
Issue number1
StatePublished - Jan 2006


  • APP/PS1 transgenic mouse
  • Alzheimer's disease
  • Amyloid-β oligomers
  • Trace fear conditioning
  • β-secretase

ASJC Scopus subject areas

  • General Neuroscience


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