NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease
Nicholas H. Varvel, … , Bruce T. Lamb, Karl Herrup
Nicholas H. Varvel, … , Bruce T. Lamb, Karl Herrup
Published November 9, 2009
Citation Information: J Clin Invest. 2009;119(12):3692-3702. https://doi.org/10.1172/JCI39716.
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Research Article Neuroscience

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

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.

Authors

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

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Figure 7

Therapeutic trial of NSAIDs inhibits subsequent, but not extant, neuronal CCEs.

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Therapeutic trial of NSAIDs inhibits subsequent, but not extant, neurona...
(A) Neuronal CCEs were first observed in frontal cortical layers II/III at 6 months of age and persisted for 2 or more years in the R1.40 animals. Neuronal CCEs were not observed in deeper cortical layers V/VI until 12 months of age. (B–M) R1.40 transgenic mice at 6 months of age were fed control (B, C, H, and I), ibuprofen-containing (D, E, J, and K) or naproxen-containing (F, G, L, and M) diets for 6 months. (B and H) Control diet–fed mice exhibited expression of cyclin D (large arrows) in NeuN-positive neurons in frontal cortex layers II/III and layers V/VI. (D, F, J, and L) Ibuprofen- or naproxen-containing diet–fed mice exhibited expression of cyclin D in a subset of NeuN-positive neurons in layers II/III (D and F), with minimal expression of cyclin D in layers V/VI (J and L). (C, E, G, I, K, and M) Merged images. Sections were stained with NeuN (red), and nuclei were counterstained with DAPI (blue). FISH analysis with a DNA probe specific for mouse chromosome 16 demonstrated the presence of a subset of neuronal nuclei with 3 or 4 spots of hybridization (small arrows) in all treatment groups in cortical layers II/III (C, E, and G, insets) and only the control diet group in cortical layers V/VI (I, K, and M, insets). Scale bars: 100 μm (B–M); 10 μm (insets).