The db mutation improves memory in younger mice in a model of Alzheimer's disease

Le Zhang, Sun Ok Fernandez-Kim, Tina L. Beckett, Dana M. Niedowicz, Katharina Kohler, Kalavathi Dasuri, Annadora J. Bruce-Keller, M. Paul Murphy, Jeffrey N. Keller

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Leprdb/db) induces mixed or vascular dementia in mature to middle-aged APPΔNL/ΔNL x PS1P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD.

Original languageEnglish
Pages (from-to)2157-2167
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number9
StatePublished - Sep 1 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier B.V.


  • Alzheimer's disease
  • Aβ synthesis
  • Cognitive function
  • Db mutation
  • Glucose regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


Dive into the research topics of 'The db mutation improves memory in younger mice in a model of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this