Amyloid Beta and Collagen IV Interactions in the Brain Microvasculature in Alzheimers Disease - Abstract/Summary Microvascular (MV) changes occur early in the Alzheimer’s disease (AD) brain. Loss of MV basement membrane (BM) integrity due to alterations in Collagen IV (Col IV), a major component of BM, in particular predisposes the MV to complications such as microhemorrhages. In the MV of both AD and the related condition of congophilic amyloid angiopathy (CAA), levels of Col IV vary and deposition of amyloid beta (Ab) is in close spatial proximity, but specific interactions between Col IV and Ab are not known. Notably, we recently found that the Ab binding antibody, lecanemab (BAN2401), causes degradation of MV Col IV. Thus, we hypothesize that Ab deposition induces structural and/or enzymatic processes that result in MV BM Col IV destabilization, and that subsequent removal of Ab by lecanemab results in Col IV breakdown, causing MV dysfunction. Brain Col IV is restricted to the vascular BM, and requires models that retain native Col IV and Ab to advance understanding of MV extracellular matrix (ECM). We propose 3 feasible aims to elucidate the interactions of Ab and Col IV in AD. Since little is known about the associations of Ab and Col IV in AD, Aim 1 will define the ultrastructural/spatial relationships among Ab, Col IV, and mediators of Col IV degradation in MV of AD/CAA and control brain sections, and in matched viable human brain MV (huMV). Aim 2 will use the 5xFAD mouse model of MV Ab to determine if/how Ab deposition, and subsequent Ab removal, affects Col IV and subsequent MV function in a mouse model of microvascular Ab. Aim 3 leverages a unique repository of viable human brain MV from AD/CAA and controls to define how modifying Ab by 2 different methods: the Ab binding antibody, lecanemab, and breaker peptides, a small molecule non-antibody mediated method of removing Ab, effects changes in Col IV and the neurovascular unit (NVU). Impact: Completion of this project will advance the understanding of brain MV Col IV interactions with Aβ that are likely important in mediating MV dysfunction in the context of AD/CAA progression. In addition, our project offers mechanistic insight on the adverse effects of Aβ-lowering therapies, which is needed for advancements to improve their safety.
