Affiliations: [a] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA | [b] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA | [c] Department of Neurology, University of California, Irvine, CA, USA
Correspondence:
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Correspondence to: Kim N. Green, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 3226 Biological Sciences 3, Irvine, CA 92697-4545, USA. Tel.: +1 949 824 3859; Fax: +1 949 824 7356; E-mail: kngreen@uci.edu.
Abstract: Cognitive decline in Alzheimer's disease (AD) occurs as a result of the buildup of pathological proteins and downstream events including an elevated and altered inflammatory response. Inflammation has previously been linked to increased abnormal phosphorylation of tau protein. To determine if endogenous amyloid-β (Aβ)-induced neuroinflammation drives tau phosphorylation in vivo, we treated 8-month-old 3xTg-AD with minocycline, an anti-inflammatory agent, to assess how it influenced cognitive decline and development of pathology. 4 months of treatment restored cognition to non-transgenic performance. Inflammatory profiling revealed a marked decrease in GFAP, TNFα, and IL6 and an increase in the CXCL1 chemokines KC and MIP1a. Minocycline also reduced levels of insoluble Aβ and soluble fibrils. Despite reducing levels of the tau kinase cdk5 coactivator p25, minocycline did not have wide effects on tau pathology with only one phospho-epitope showing reduction with treatment (S212/S214). The sum of these findings shows that reduction of the inflammatory events in an AD mouse model prevents cognitive deficits associated with pathology, but that endogenous Aβ-derived neuroinflammation does not contribute significantly to the development of tau pathology.
Keywords: Alzheimer's disease, cognition, inflammation, p25, tau phosphorylation, therapeutic
