Cerebral accumulation of the A peptide in amyloid plaques is an early pathological hallmark of AD and likely triggers neuroinflammation and tau pathology in the disease. Understanding the cause A accumulation and its effects in the brain are necessary for discovery of AD diagnostic biomarkers and disease-modifying therapies. A is generated via sequential proteolysis of the amyloid precursor protein (APP) by the enzymes -secretase (BACE1) and -secretase. BACE1 is the rate-limiting enzyme for A production. APP and BACE1 are increased by physiological stress and injury conditions that exacerbate amyloid pathology. Astrocytes are crucial glial cells in the brain that react to microglia and amyloid pathology. On the one hand, we have shown that APP, BACE1, and A production are elevated in astrocytes by proinflammatory cytokines IL-1, TGF-, and IFN-, which may contribute to amyloidosis. On the other hand, it is conceivable that under some circumstances astrocytes secrete insulin degrading enzyme (IDE) or neprilysin (NEP), enzymes that clear A. Astrocytes are part of the innate immune system and are strongly affected by microglial cells. Indeed, activated microglia release proinflammatory cytokines that induce the A1 subtype of neurotoxic reactive astrocyte. However, the role of astrocytes, their interaction with microglia, and the affect of the microbiome on astrocytes in AD are poorly understood. Based on Dr. Sisodia’s and Tanzi’s work, we hypothesize that pathogenic microbiota in the gut and brain lead to elevated numbers of A1 astrocytes, perhaps via induction by microglia, resulting in negative consequences like neurotoxicity, increased levels of astrocytic APP, BACE1 and A generation, or decreased A clearance. The gut microbiome may signal to microglia in the brain via blood-borne cytokines, while the brain microbiome may directly interact with microglia and astrocytes. These processes could be affected by ApoE, TREM2, CD33, and other AD risk genes (Dr. Holtzman’s work) or a dysfunctional blood-brain barrier (BBB; Dr. Zlokovic’s work). In Project 4, we will investigate how the microbiota affect the astrocyte transcriptome, translatome, and metabolome in ways that could be important for AD pathogenesis. In summary, we anticipate that our studies should elucidate the interactions of genetic risk factors and gut microbiota in mediating the astroglial inflammatory phenotypes that impact Aβ pathology. Understanding of the role of the microbiome in modulating astroglial function in AD may facilitate the discovery of new targets, pathways, and molecular mechanisms that could be exploited for the development of disease modifying AD therapies.
|Effective start/end date||10/25/18 → 12/31/21|
- Good Ventures Foundation (Agmt 10/25/18)