Abstract 106: Vascular Dysfunction In The Mesenteric Resistance Arteries Occurs Prior To The Occurrence Of Early-onset Alzheimer’S Disease In A Sex-dependent Manner

Abstract

Alzheimer’s Disease (AD) and cardiovascular diseases (CVDs) are a major cause ofdisability and death among the older population. Familial Alzheimer’s Disease (FAD) islinked with an early onset AD (EOAD) pathology (<65years) that manifests throughpathogenic mutations in the presenilin (PSEN)1 and PSEN2 genes, leading to theincreased production of central amyloid β (Aβ) peptides. There is increasing evidencethat elevated blood pressure and peripheral arterial stiffness contribute to thedevelopment and increase the risk of β-amyloid deposition in the brain leading to cognitivedecline later in life. We hypothesized that peripheral vascular remodeling and vasculardysfunction in the aorta and mesenteric resistance arteries (MRA) would be observedprior to the development of EOAD. The MRA of male and female C57Bl/6J (control) andAD mice (B6. CApptm1DboTg(APPswe,PSEN1dE9)85Dbo) at 9-weeks-old were isolatedprior to the onset of AD. Acetylcholine-induced relaxation (1pM-30μM) andphenylephrine-induced contraction (0.1nM-30μM) were evaluated using wire myography.Pulse wave velocity (PWV) and H&E staining were used to measure vascular stiffnessand morphology, respectively. Data were analyzed as non-linear curve regression andmaximum response (Rmax) using the Student t test ( p <0.05*). MRA from AD miceshowed impaired relaxation in both males (Rmax: control 90±0.9 vs. AD 59±6.4* %, n=3-4) and females (Rmax: control 90±2.8 vs. AD 70±8.3*%, n=4-6). Interestingly,phenylephrine-induced contraction was reduced in arteries from males (Rmax: control11.7±0.9 vs . AD 7.7±0.8* mN, n=3-4), but not in arteries from females (Rmax: control9.3±1.3 vs. AD 8.1±0.6 mN, n=6-7). However, no differences were observed in the aortawall thickness in the male (control 51.8±2.9 vs. AD 72±9.2 μm, n=3-4), or female (control63.7±9.8 vs. AD 54±4.8μm, n=2-3) AD mice, as well as the PWV analysis from male ADmice (control 2.41±0.44 vs. AD 4.05±1.4 mm/ms, n=6). These data suggest that thechanges observed in the peripheral microvasculature prior to the onset of AD could laterhave direct effects on cerebral blood flow leading to areas of altered blood perfusion andmicrovascular damage, thus contributing to the genesis and maintenance of AD.