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)
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Special Emphasis Panel (ZAG1)
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Petanceska, Suzana
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University of Florida
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Miller, Jeremy A; Guillozet-Bongaarts, Angela; Gibbons, Laura E et al. (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife 6:
Ridge, Perry G; Karch, Celeste M; Hsu, Simon et al. (2017) Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience. Genome Med 9:100
Sims, Rebecca (see original citation for additional authors) (2017) Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet 49:1373-1384
Allen, Mariet; Wang, Xue; Burgess, Jeremy D et al. (2017) Conserved brain myelination networks are altered in Alzheimer's and other neurodegenerative diseases. Alzheimers Dement :
N'Songo, Aurelie; Carrasquillo, Minerva M; Wang, Xue et al. (2017) African American exome sequencing identifies potential risk variants at Alzheimer disease loci. Neurol Genet 3:e141
N'Songo, Aurelie; Carrasquillo, Minerva M; Wang, Xue et al. (2017) Comprehensive Screening for Disease Risk Variants in Early-Onset Alzheimer's Disease Genes in African Americans Identifies Novel PSEN Variants. J Alzheimers Dis 56:1215-1222
Allen, Mariet; Lincoln, Sarah J; Corda, Morgane et al. (2017) ABCA7 loss-of-function variants, expression, and neurologic disease risk. Neurol Genet 3:e126
Futch, Hunter S; Croft, Cara L; Truong, Van Q et al. (2017) Targeting psychologic stress signaling pathways in Alzheimer's disease. Mol Neurodegener 12:49
Carrasquillo, Minerva M; Barber, Imelda; Lincoln, Sarah J et al. (2016) Evaluating pathogenic dementia variants in posterior cortical atrophy. Neurobiol Aging 37:38-44
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

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