ALZHEIMERS RESEARCH PROJECT - Impact of atherosclerosis-induced cellular senescence on vascular cognitive impairment and dementia (VCID) (Alzheimers disease)

National Institute On Aging

Investigators

Abstract

In the previous year, our study aimed to investigate the effects of atherosclerosis and the use of senolytics during atherosclerosis on VCID in young mice (~4-6 months old). In our published study, we observed that atherosclerotic mice developed increased senescent cell burden in the aorta, mainly VSMCs, fibroblasts, and T cells. These senescent cells contributed to pathological arterial remodeling, resulting in increased necrotic core area, reduced fibrous cap thickness, reduced collagen accumulation, and increased arterial stiffening. All these pathologies were improved by senolytic treatment, implicating senescent cells in the pathological processes and their removal improved physiological remodeling. We observed behavioral abnormalities in anxiety and long-term spatial memory that were influenced by atherosclerosis, age, and/or senolytic drug treatment; therefore, we next sought to determine regions of the brain impacted by atherosclerosis-induced senescence in young and old male atherosclerotic mice by treating with senolytics (Objective 1), whether senolytic drugs improves cognition in old mice (Objective 2), and if changes observed in mice can be correlated to changes in human cognitive decline from various studies (Objective 3). We are currently performing spatial transcriptomic sequencing on the brains from control, atherosclerotic, and atherosclerotic mice treated with a senolytic drug to determine the regions most impacted by senescence. To do so, we have devised a strategy in which we will examine transcriptomic profiles associated with astrocytes (GFAP+), oligodendrocytes (Olig2+), microglia (Iba1+), and neurons (NeuN+) (Objective 1). Additionally, we have performed nanoparticle-based proteomics on the serum of these mice and have linked senolytic-responsive proteins with neurocognitive outcomes such as increased correlation with dementia risk (Objective 3). Lastly, we performed a similar experiment, as previously described, on young and old wild-type mice treated with and without the senolytic drug fisetin. Interestingly, we observed no change in many cognitive phenotypes; however, old male mice treated with fisetin showed improved arterial stiffness and grip strength. Young female mice also experienced improved grip strength with the senolytic treatment (Objective 2). We are also utilizing MRI imaging of the brains from these groups to determine changes in structure and function with VCID and senolytic treatment. Mass spectrometry on whole brain lysates from these animals revealed that old male and female mice treated with fisetin had increased protein expression related to mitochondrial function, while males also showed reduced lysosomal activity, and females had reduced levels of complement and coagulation proteins, which we previously linked to vascular senescence.