Thursday, November 21, 2024
11/21/2024
Apolipoprotein E4 (ApoE4) is recognized as a strong risk factor for the development of late-onset Alzheimer’s disease (LOAD). To better understand the impact of ApoE genotype on the emergence and progression of LOAD and to effectively evaluate therapeutic interventions for this condition appropriate experimental animal models are needed. To date, most animal model studies designed to address the contributions of ApoE genotype to AD have largely centered around the use of transgenic mice. Typically, most transgenic lines for AD rely on highly artificial over-expression of transgenes and largely incorporate one or more early-onset FAD mutations in AbPP or presenilin. Moreover, transgenic animals are prone to developmental and insertional effects on the host genome and are susceptible to loss of transgene expression and genetic drift in subsequent generations. In addition to these caveats, another major shortcoming of transgenic lines is that any AD pathology that develops typically is from a ‘sole source’ of transgene expression. In most cases, the ‘sole source’ of transgenic proteins results from strong over-expression in neuronal cells. With regards to AD, it is known that besides neurons neighboring astrocytes and microglia can express AbPP, produce Ab peptides and participate in AD pathogenesis. In addition, vascular cell types including endothelial cells, smooth muscle cells and pericytes all express AbPP, produce Ab peptides and reside at the site of CAA, a common vascular co-morbidity of LOAD. Since the complexity of the cellular origins of Ab in AD are not captured in ‘sole source’ transgenic models they fail to reveal the true pathogenesis of this disorder and an accurate understanding of the impact of ApoE. This glaring shortcoming has prompted the quest to generate better experimental animal models for LOAD that more fully capture the pathogenesis of this condition and more accurately reflect human disease. The overall goal of this exploratory proposal is to study the impact of ApoE genotype on the emergence and progression of LOAD pathologies and cognitive impairment using a novel gene-edited rat model (CrHuAb) used to generate bigenic CrHuAb/hApoE3 and CrHuAb/hApoE4 rats. These novel and timely rats will provide superior, state-of-the-art preclinical models that will more realistically reflect the true pathogenesis of LOAD that develops in patients compared to transgenic mice commonly used in the field.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
