Cervical lymphatic vessel dysfunction induced by amyloid-β and in the 5x-FAD mouse model of Alzheimer’s disease

Alzheimer’s dementia is a multifactorial disease characterized by amyloid-β (Aβ) accumulation in the brain. Aβ clearance occurs partially via meningeal lymphatics into cervical lymph nodes through superficial cervical lymphatic vessels (sCLV), which relies on intrinsic contractions of sCLV. Previous studies showed increased Aβ build up in the brain following ablation of meningeal lymphatics; however, whether Aβ alters sCLV function remains unclear. We hypothesize that sCLV contractile function will be reduced by acute Aβ exposure and in the 5x-FAD mouse model of Alzheimer’s disease. Contractile function of freshly isolated sCLV was assessed using pressure myography. Acute Aβ exposure was achieved by intraluminal incubation of pressurized sCLV with Aβ (1-40) (5 μM) or vehicle for 15 minutes prior to the start of the experiment. Repeated end-diastolic (EDD) and end-systolic (ESD) measurements were used to calculate fractional pump flow (FPF), the product of contractile frequency (FREQ) measured as contractions per minute (Hz), and ejection fraction (EF) calculated as (EDD 2 -ESD 2 )/EDD 2 , at incremental intraluminal pressures ranging from 2 to 10 cmH 2 O. Statistical differences were determined by two-way ANOVA followed by Sidak correction for multiple comparisons. All data are means ± SEM. In sCLV isolated from 5 months-old males and females C57bl/6J mice, acute Aβ exposure significantly decreased FREQ (Vehicle vs Aβ, n=4 / n=7, p<0.01), without changes in EF (Vehicle vs Aβ, n=4 / n=7, p=0.115) or FPF (Vehicle vs Aβ, n=4 / n=7, p= 0.536). In pressurized sCLV isolated from 5x-FAD mice, when compared to wild-type littermates, we observed a significant reduction in FREQ (Wild-type vs 5x-FAD, n=4 / n=5, p<0.01). No differences were observed in EF (Wild-type vs 5x-FAD, n=4 / n=5, p=0.1224) or FPF (Wild-type vs 5x-FAD, n=4 / n=5, p=0.193). Together, these preliminary data suggest that acute exposure to Aβ (1-40) decreases FREQ of isolated sCLV, a similar effect observed in sCLV isolated from 5x-FAD mice, albeit not reaching statistical power for multiple comparison significance. Consequently, a decrease contractile frequency can contribute to impairments in lymphatic pumping, which to some extent, can be compensated by prolonged filling times, thus leading to increased ejection fraction. In conclusion, we predict that in vivo sCLV contractile function is maintained via compensatory increases in ejection fraction in conditions of exacerbated Aβ production and deposition. Funding: National Institutes of Health (R01 AG073230) and the Alzheimer’s Association (AARGD-21-850835). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.