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

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

doi:10.1111/j.1460-9568.2005.04551.x

Cited by 298Alzheimer's disease research and treatmentsMemory and Neural MechanismsDementia and Cognitive Impairment Research

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

Ohno, Masuo, Chang, Lei, Tseng, Wilbur, Oakley, Holly, Citron, Martin, Klein, William L., Vassar, Robert, Disterhoft, John F.·2006·European Journal of Neuroscience

DOI 10.1111/j.1460-9568.2005.04551.x

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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.

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Tg6799 mice have also been tested in trace and contextual fear conditioning paradigms and the Morris water maze, and they also exhibited deficits in these other hippocampus-dependent memory tasks.
“Tg6799 mice have also been tested in trace and contextual fear conditioning paradigms and the Morris water maze, and they also exhibited deficits in these other hippocampus-dependent memory tasks (Ohno et al., 2006).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Ohno et al., 2006
No significant differences in hippocampus-independent cued fear response were observed between 5xFAD, 5xFAD LRP1BE−/−, and wildtype littermates, irrespective of PCSK9 inhibition or control treatment.
“no significant differences between 5xFAD, 5xFAD LRP1BE−/−, and wildtype littermates were observed, irrespective of PCSK9-inhibition or control treatment (Fig. 6B).”
From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [41]
Significant memory impairment is observed in 5XFAD mice before six months of age.
“Significant memory impairment is observed before six months of age [35,37,38]”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [38]
Reduced hippocampus-dependent trace fear conditioning, but normal hippocampus-independent delay fear conditioning, comparable to the tone memory assayed here, has been reported for 5XFAD mice.
“Reduced hippocampus dependent trace fear conditioning, but normal hippocampus independent delay fear conditioning, which is comparable to the tone memory assayed here, has been reported for 5XFAD mice [47].”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [47]

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Authors: Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W. L., Vassar, R., & Disterhoft, J. F.
Affiliations: Northwestern University (US)
Amgen (United States) (US)
ORCID: Ohno, Masuo
Chang, Lei
Oakley, Holly
Citron, Martin
Klein, William L.
Vassar, Robert
Disterhoft, John F.
Venue: European Journal of Neuroscience
Publisher: Wiley
Published: 2006-01
Volume: 23
Issue: 1
Pages: 251-260
ISSN: 0953-816X (ISSN-L)
1460-9568
DOI: 10.1111/j.1460-9568.2005.04551.x
OpenAlex: W2093419961
Cited by: 298
References: 62
Citations by year: 2026: 3 · 2025: 13 · 2024: 19 · 2023: 13 · 2022: 15 · 2021: 14 · 2020: 13 · 2019: 14 · 2018: 6 · 2017: 18 · 2016: 16 · 2015: 17 · 2014: 22 · 2013: 15 · 2012: 21
FWCI: 10.87
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 17 d)
Locations: European Journal of Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (R37AG011385, R37AG008796, R01AG022560, R01AG022547)
National Institute of Mental Health (R01MH067251)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, temporal memory, BACE1, amyloid-beta oligomers, trace fear conditioning, hippocampal-dependent memory, APP/PS1 mice, Tg2576 mice, beta-secretase inhibition, amyloid-beta deposition
MeSH terms: Alzheimer Disease, Analysis of Variance, Animals, Conditioning, Psychological, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Fear, Membrane Proteins, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Endopeptidases, Immunoblotting, Blotting, Western, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Maze Learning, Mice, Presenilin-1, Amyloid Precursor Protein Secretases

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

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