Chiduruppa, V. | bioRxiv Science

bioRxiv2025

Telmisartan and Lisinopril Show Potential Benefits in Rescuing Cognitive-Behavioral Function Despite Limited Improvements in Neuropathological Outcomes in Tg-SwDI Mice

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease that results from beta-amyloid (A{beta}) accumulation in the vessel walls that is associated with cognitive impairment and other neurological pathologies. There are currently no medications approved to treat CAA. This study investigated whether renin-angiotensin system (RAS)-targeting drugs, commonly prescribed to treat hypertension, can be repurposed to treat CAA, and whether their effects differ by sex. Male and female Tg-SwDI mice were treated for 5 months with sub-depressor doses of either telmisartan [angiotensin II receptor blocker (ARB)] or lisinopril [angiotensin-converting enzyme (ACE) inhibitor] starting at 3 months of age. Blood pressure monitoring was performed 2 and 4 months after the start of treatment, followed by behavior testing at 7 months of age. Histochemical analyses were conducted to determine vasculopathy, A{beta} pathology, and neuroinflammation (microgliosis and astrogliosis). Outcomes in drug-treated and untreated Tg-SwDI mice were compared to each other and with wild-type (C57BL/6J) controls. Overall, both drugs were able to rescue some cognitive-behavioral functions; however, no reductions in A{beta} levels were observed, and only limited improvements in vascular density and neuroinflammatory markers were detected. Notably, some treatment effects varied with sex, the specific behavioral task, and the brain region analyzed. These findings support the hypothesis that RAS-targeting drugs exert neuroprotective effects through mechanisms beyond blood pressure control offering a promising therapeutic avenue for CAA.

neuroscience↗

bioRxiv2025

Ketogenic Diet Enhances Cognitive-Behavioral Function and Hippocampal Neurogenesis While Attenuating Amyloid Pathology in Tg-SwDI Mice

The ketogenic diet (KD), characterized by high-fat, low-carbohydrate, and moderate protein intake, has gained attention for its therapeutic potential in patients with neurodegenerative diseases, including Alzheimers disease. Studies in Alzheimers rodent models report that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, amyloid-beta plaques and tau pathology. However, it is unknown whether KD can similarly benefit individuals with cerebral amyloid angiopathy (CAA), a prevalent condition in which amyloid accumulates in cerebral vessels. CAA is highly comorbid in patients with Alzheimers and, on its own, increases the risk of stroke, cognitive impairment, and dementia, yet no effective treatments currently exist. The objective of this study was to determine whether KD can improve cognitive-behavioral and neuropathological outcomes in a mouse model with CAA. Male Tg-SwDI mice were fed either a standard chow or KD from 3.5 to 7.5 months of age. Following [~]3 months of dietary intervention, glucose and ketone-body levels were assessed, then mice underwent a battery of behavioral tests to evaluate locomotor activity, anxiety-related behaviors, and cognition. Immunohistochemistry was performed to assess amyloid pathology, vascular density, neuroinflammation, white matter integrity, and hippocampal neurogenesis. In addition to KD inducing nutritional ketosis and achieving metabolic benefits, mice on KD exhibited increased activity, enhanced spatial learning and memory, and a trend toward improved spatial working memory. These cognitive benefits were accompanied by an attenuation of amyloid pathology and increased hippocampal neurogenesis. These findings suggest that a ketogenic diet may be safe and effective in Alzheimers and dementia patients with CAA.

neuroscience↗