R01AG075840

Role of Microglia in Neurodegeneration - Effect of ApoE - Project Summary

Like Alzheimer's disease, prion diseases (prionoses) are conformational disorders in which the deposition of misfolded proteins is accompanied by a neurodegenerative phenotype in microglia (MGND), displaying mixed phagocytic and inflammatory properties.

Prion mouse models with misfolded protein-driven neurodegeneration and activated glia response can be used to uncover Alzheimer's disease relevant pathomechanisms. The ApoE E4 allele is the foremost risk factor in sporadic Alzheimer's disease, increasing its odds by 3 and 15-fold in hetero and homozygotes, respectively.

ApoE encodes apolipoprotein (APO) E, which controls brain lipid homeostasis and modulates Alzheimer's disease risk through isoform-specific effects on clearance and deposition of soluble amyloid beta (Aβ) species. ApoE is expressed by astrocytes in the form of ApoE/HDLS and also by MGND as lipid-poor particles. The differential contributions of these two ApoE pools to MGND properties remain unclear. While lipidated ApoE may facilitate the clearance of misfolded proteins, the expression of lipid-poor ApoE by MGND is linked to their pro-inflammatory properties, which are also differentially controlled by ApoE genotype.

In prionoses, the accumulation of toxic PrPSc protein is the culprit of pathogenesis. Microglia undergo activation early in the course of the disease and exert opposing roles in PrPSc-mediated neurodegeneration. While clearance of PrPSc has a disease-limiting effect, microglia-driven neuroinflammation is deleterious to neurons. Involvement of ApoE in prion pathogenesis has not been established, though there is evidence for approximately a 2-fold higher risk of sporadic Creutzfeldt-Jakob disease (CJD) in E4 carriers.

Our preliminary work shows increased brain ApoE levels in prion-infected mice, along with reduced ApoE expression in astrocytes and increased expression in activated microglia. The overall effect of ApoE in prionoses is beneficial, as global ApoE knockout exacerbates prion pathology by aggravating the vicious cycle of neuronal death and neuroinflammation. In ApoE-/- mice, clearance of PrPSc and dying neurons by MGND becomes inefficient, while neuronal debris exaggerates MGND phenotype, release of inflammatory cytokines, and induce A1 neurotoxic astrocytes. Our studies also suggest that the ApoE effect in prionoses is isoform-dependent. E4/E4 targeted replacement (TR) mice have a shorter disease incubation time, increased pathology load, and microglia hyperactivation compared to E3/E3 and E2/E2 mice.

This preliminary work led us to hypothesize that 1) ApoE involvement in prion pathogenesis is by controlling microglia response to PrPSc-mediated neurodegeneration; 2) ApoE-based approaches have therapeutic merit in prionoses; and 3) the effect of ApoE in human prionoses is isoform-dependent. These hypotheses shall be explored in the grant's specific aims.

Aim I will assess the role of astrocyte vs. microglia-expressed ApoE on PrPSc-mediated neurodegeneration in mice with cell-specific conditional ApoE knockout. Aim II will assess whether regulating the lipidation level of astrocytic and microglial ApoE and the total brain ApoE level modulates neurodegeneration. Aim III will explore the effects of ApoE genotype on microglia activation phenotype in prion-infected ApoE TR mice and in sporadic CJD and Alzheimer's disease patients.

New York University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New York, New York 10016 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 374% from $725,104 to $3,433,626.