NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease

Nicholas H. Varvel, Kiran Bhaskar, Maria Z. Kounnas, Steven L. Wagner, Yan Yang, Bruce Lamb, Karl Herrup

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Ectopic cell cycle events (CCEs) mark vulnerable neuronal populations in human Alzheimer disease (AD) and are observed early in disease progression. In transgenic mouse models of AD, CCEs are found before the onset of β-amyloid peptide (Aβ) deposition to form senile plaques, a hallmark of AD. Here, we have demonstrated that alterations in brain microglia occur coincidently with the appearance of CCEs in the R1.40 transgenic mouse model of AD. Furthermore, promotion of inflammation with LPS at young ages in R1.40 mice induced the early appearance of neuronal CCEs, whereas treatment with 2 different nonsteroidal antiinflammatory drugs (NSAIDs) blocked neuronal CCEs and alterations in brain microglia without altering amyloid precursor protein (APP) processing and steady-state Aβ levels. In addition, NSAID treatment of older R1.40 animals prevented new neuronal CCEs, although it failed to reverse existing ones. Retrospective human epidemiological studies have identified long-term use of NSAIDs as protective against AD. Prospective clinical trials, however, have failed to demonstrate a similar benefit. Our use of CCEs as an outcome measure offers fresh insight into this discrepancy and provides important information for future clinical trials, as it suggests that NSAID use in human AD may need to be initiated as early as possible to prevent disease progression.

Original languageEnglish (US)
Pages (from-to)3692-3702
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number12
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

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Cell Cycle
Alzheimer Disease
Anti-Inflammatory Agents
Pharmaceutical Preparations
Microglia
Transgenic Mice
Disease Progression
Clinical Trials
Protective Agents
Amyloid beta-Protein Precursor
Amyloid Plaques
Brain
Vulnerable Populations
Amyloid
Epidemiologic Studies
Outcome Assessment (Health Care)
Inflammation
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. / Varvel, Nicholas H.; Bhaskar, Kiran; Kounnas, Maria Z.; Wagner, Steven L.; Yang, Yan; Lamb, Bruce; Herrup, Karl.

In: Journal of Clinical Investigation, Vol. 119, No. 12, 01.12.2009, p. 3692-3702.

Research output: Contribution to journalArticle

Varvel, Nicholas H. ; Bhaskar, Kiran ; Kounnas, Maria Z. ; Wagner, Steven L. ; Yang, Yan ; Lamb, Bruce ; Herrup, Karl. / NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 12. pp. 3692-3702.
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