Alzheimer's disease (AD) is the leading cause of dementia, affecting more than 5 million older people in the U.S. alone. It is imperative to define the earliest cellular functions and molecular mechanisms driving the earliest pathogenesis in prodromal AD, mild cognitive impairment (MCI). Microglia, the primary brain immune cells, have been implicated as playing an important role in the development of AD. Genetic studies indicate that genetic risk factors associated with the disease are highly expressed in microglia. TREM2, a receptor expressed exclusively on microglia, is at the top of the risk gene list. In response to A? deposition, microglia become activated and adopt a series of gene expression profiles and pathways specifically linked to neuroinflammation. Activated microglia release pro-inflammatory cytokines and neurotoxic proteins that cause pathologic neurodegeneration. Therefore, microglial gene signaling is believed to serve as a key regulator that allows microglia to switch from a homeostatic to a disease-associated state. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage, and the exact cellular functions and molecular mechanisms are unknown due to the lack of a microglia model of the disease continuum. In this study, we propose using advanced tools (a patient-specific microglia model and engineered protein chimeras) to study microglial gene regulation and phagocytic activities during prodromal AD (MCI). Our long-term goal is to develop novel disease-modifying therapies for early intervention for AD. Our hypothesis is that microglial gene expression and phagocytosis play important roles in the early development of AD. To test this hypothesis, we propose two pilot projects for this proposal. Project 1: Patient-specific induced microglial modeling of gene regulation for prodromal AD (MCI). Project 2: TREM2-mediated phagocytic clearance of A? amyloid in mice. The patient-specific microglia model would vastly accelerate the rate of discovery of genes, pathways, and functions associated with AD. With this cellular model, in conjunction with the AD studies supported by the CNTN COBRE, we will be able to dissect the microglia molecular signatures linked to A? pathology and their functional changes to shed light on the pathology of AD. Focusing specifically on patients with MCI rather than AD will allow us to understand the mechanisms inherent in early-stage disease instead of focusing on syndromic dementia when the disease is more resistant to therapy. Moreover, harnessing the therapeutic potential of protein chimeras designed to facilitate anti-inflammatory microglial phagocytosis of ?-amyloid via TREM2 may prevent microglial activation and will result in a reduced immune response. If successful, the protein chimeras will be tested as a potential therapy for AD. The proposed collaborative studies will stimulate additional collaborations among project leaders, cores, and COBREs and will further advance career development of the COBRE junior investigators.
Alzheimer's disease is a common, complex, very costly and often devastating condition with an increasing prevalence as the population ages. Although the symptoms of Alzheimer's disease typically begin with subtle changes in episodic memory, underlying biological changes may occur over several decades prior to symptom onset. Microglia, the brain macrophage, play an important role in the disease development. Using a well- characterized microglia and animal models, we will study microglia gene expression, TREM2 or other pathways, and phagocytosis for better understanding of early disease stages which will be critical for development of early targeted intervention.
| Sharma, Surbhi; Young, Richard J; Chen, Jingchun et al. (2018) Minimotifs dysfunction is pervasive in neurodegenerative disorders. Alzheimers Dement (N Y) 4:414-432 |
| Xiao, X; Roohani, D; Wu, Q (2018) Genetic profiling of decreased bone mineral density in an independent sample of Caucasian women. Osteoporos Int 29:1807-1814 |
