Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the third major cause ofdeath in the United States. AD is characterized and diagnosed by distinctive neuropathological alterationsincluding extracellular deposits of the ?-amyloid (A?) peptide intraneuronal aggregates of the microtubuleassociated protein tau (MAPT) and marked neuroinflammation. However, the exact mechanistic relationshipbetween neuroinflammation and the various brain pathologies and clinical outcomes in AD remains unclear aswell as the respective roles of brain resident microglia and infiltrating peripheral immune cells in theseprocesses. Recent genetic and system biology studies have implicated multiple innate immune signalingpathways in late-onset AD. Most importantly, rare heterozygous coding mutations in TREM2, a geneexclusively expressed by myeloid cells were identified that substantially increase risk for AD and otherneurodegenerative diseases. Our preliminary findings demonstrate that TREM2 is upregulated in mousemodels of AD with A? pathology and human AD. Furthermore, co-localization studies demonstrated thatTREM2 is selectively upregulated within myeloid cells in close proximity to A? deposits, but not in myeloid cellsfurther away from A? deposits. Strikingly, careful flow cytometry and immunohistochemical analyses of brainsfrom mouse models of AD revealed that TREM2 is upregulated within cells that bear markers reflective of theirpotential origin from circulating inflammatory monocytes. Consistent with these findings, preliminary analysisrevealed an increase in TREM2+ cells in human AD blood samples. Furthermore, TREM2 deficiency in an ADmouse model leads to a virtual absence of the myeloid cells surrounding A? deposits and an overall reductionin AD-like pathologies. Finally, nuclear receptor agonists selectively target these plaque-associated TREM2+cells and promote phagocytosis. The hypothesis to be tested in the current collaborative andinterdisciplinary studies is that brain resident microglia and blood-derived TREM2+ inflammatorymonocytes play distinctive roles in regulating AD pathologies that could provide novelbiomarkers/diagnostics and also be targeted therapeutically. These studies will utilize state-of-the artmouse models of AD, constitutive Trem2 knockout mice, transgenic mice enabling deletion of TREM2 invarious myeloid cell populations, detailed flow cytometry and genome-wide gene expression analyses as wellas neuropathology and behavior to examine the three Specific Aims of the proposal: 1. Examine the Identity, Localization and Gene Expression Profiles of TREM2+ Cells in Mouse Models and Human AD. 2. Determine the Central and Peripheral Role of TREM2 in Regulating AD Pathologies. 3. Therapeutically Targeting TREM2+ Cells
Multiple recent studies have demonstrated that the TREM2 gene; and innate immunity more generally;plays a critical role in the pathogenesis of neurodegenerative diseases; including AD. However; itremains unclear in which cell populations (microglia; monocytes; etc.) TREM2 acts; the exact role ofTREM2 in regulating neurodegenerative disease pathologies. The current interdisciplinary studies seek toexamine whether brain resident microglia and blood-derived TREM2+ monocytes play distinctive roles inregulating AD pathologies and whether the TREM2+ cell population could provide novelbiomarkers/diagnostics and be targeted therapeutically.
