An invariant feature of the pathological cascade in Alzheimer's diseases (AD) is a reactive gliosis, reflecting an underlying alteration in the innate immune activation state within the brain. Innate immune signaling is altered early in AD, but is also skewed towards an activated state as a consequence of brain aging. There is strong genetic evidence that innate immunity has a significant role in AD. Variants in two genetic loci that play roles in the complement cascade, CR1 and CLU, show significant genetic associations with AD, and rare coding variants in TREM2 also confer substantial risk for AD. Numerous experimental studies in AD mouse models show that manipulating innate immune pathways can have positive or negative effects on proteostasis, cognition and neurodegeneration. At least when assessing A? pathology as an endpoint, the beneficial effects of some innate immune system manipulations are robust. We propose to identify therapeutic targets within the innate immune signaling cascade in AD that could be safely manipulated to provide disease modification in AD. However, because of the complexity of, and the gaps in our knowledge regarding, innate immune signaling within the CNS, a systems level approach that integrates multiple types of data will be required to achieve this goal. Indeed, development of any innate immune therapy will need to be finely tuned and extensively validated in order to be further developed as a potential AD therapy. We will use a multifaceted systems level approach to identify targets within innate immune signaling pathways that can safely provide disease modifying effects in AD. Comprehensive, transcriptomic, genetic and pathological data from both humans and mouse models will be generated, integrated and analyzed in novel ways. This integrated data will then be used to guide multiple preclinical target validation studies of key innate immune targets in both APP and tau mouse models as well as non-transgenic mice. These studies will dramatically accelerate the identification and validation of disease modifying innate immune modulatory strategies in AD and will provide important insights into how these various manipulations of innate immune activation states alter normal behaviors with an emphasis on cognition.

Public Health Relevance

Finding effective therapy for Alzheimer's Disease is a huge unmet medical need. The proposed studies will provide key information that will guide development of innate immune therapies. They will provide the rationale and preclinical validation for further development of novel therapies harnessing innate immunity that could target multiple pathologies relevant to Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Petanceska, Suzana
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Florida
Schools of Medicine
United States
Zip Code
Caberlotto, Laura; Marchetti, Luca; Lauria, Mario et al. (2016) Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer's disease. Sci Rep 6:32583
Jun, G; Ibrahim-Verbaas, C A; Vronskaya, M et al. (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108-17
Ma, Li; Allen, Mariet; Sakae, Nobutaka et al. (2016) Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains. Mol Neurodegener 11:72
Allen, Mariet; Burgess, Jeremy D; Ballard, Travis et al. (2016) Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. Acta Neuropathol 132:197-211
Carrasquillo, Minerva M; Allen, Mariet; Burgess, Jeremy D et al. (2016) A candidate regulatory variant at the TREM gene cluster associates with decreased Alzheimer's disease risk and increased TREML1 and TREM2 brain gene expression. Alzheimers Dement :
Allen, Mariet; Carrasquillo, Minerva M; Funk, Cory et al. (2016) Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Sci Data 3:160089
Pottier, Cyril; Ravenscroft, Thomas A; Brown, Patricia H et al. (2016) TYROBP genetic variants in early-onset Alzheimer's disease. Neurobiol Aging 48:222.e9-222.e15
Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M et al. (2016) Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease. Alzheimers Dement 12:862-71
Carrasquillo, Minerva M; Barber, Imelda; Lincoln, Sarah J et al. (2016) Evaluating pathogenic dementia variants in posterior cortical atrophy. Neurobiol Aging 37:38-44
Walton, Ronald L; Soto-Ortolaza, Alexandra I; Murray, Melissa E et al. (2016) TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet 2:e85

Showing the most recent 10 out of 24 publications