Role of autoregulation of cerebral blood flow in diabetes‐related Alzheimer‐Like Cognitive Deficits
Authors: Wang Shaoxun , Yu Hongwei , Lv Wenshan , Li Longyang , Mims Paige N. , Maeda Kenji J. , Wang Yangang , Rajkowska Grazyna K. , Williams Jan M. , Paul Ian , Simino Jeannette , Auchus Alexander P. , Mosley Thomas H. , Jacob Howard , Roman Richard J. , Fan Fan 
Published: November 2023

Alzheimer's disease (AD) and diabetes (DM) are two of the most common diseases of aging. More than 5 and 29 million Americans have AD and DM, respectively. The cumulative incidence of AD and DM is 12.5% and 26.9%, respectively, among people 65 and older in the US. Evidence suggests that DM is linked with the development of AD, and both DM and AD are associated with cerebral vascular dysfunction. However, the mechanisms involved have not been fully elucidated. There is an urgent need to understand the mechanisms for the development of new therapeutic strategies to delay the onset and progression of these devastating diseases.

The T2DN rat is a type 2 DM rat model that exhibits diabetic nephropathy by 6 months of age. The present study examined whether aged T2DN rat is associated with cognitive impairment and AD‐like pathology, and whether autoregulation of cerebral blood flow (CBF) is impaired that contributes to cognitive deficits in this rat model. The levels of proteinuria (331 ± 37 vs. 36 ± 8 mg/d), glucose (392 ± 17 vs. 85 ± 4 mg/dL) and glycated hemoglobin (HbA1c, 11.5 ± 0.2 vs. 4.7 ± 0.1%) were higher in aged T2DN than control rats. CBF rose to 198 ± 10%, 153 ± 3% and 132 ± 4%, respectively, when MAP was increased from 100 to 180 mmHg, and reduced to 49 ± 2%, 68 ± 4% and 93 ± 7%, respectively, when MAP was decreased from 100 to 140 mmHg in elderly T2DN, old control rats in comparison to young control rats. Aged T2DN rats exhibit BBB leakage and AD‐like cerebral vascular remodeling. The expression of Amyloid β 42 (Aβ), p‐tau (S416), GFAP and IL‐1 beta were significantly higher in the brains of old T2DN vs. control rats. Elderly T2DN rats also displayed learning and memory dysfunction as their latency of escape was longer in an eight‐arm water maze test (T2DN 71 ± 6 secs vs. control 17 ± 3 secs in day one and T2DN 66 ± 8 secs vs. control 11 ± 1 secs in day two), and spent less time in the target arm 48 hours after training (T2DN 3 ± 3 vs. control 45 ± 2%). These findings indicate that T2DN is a diabetic rat model that is associated with an impaired autoregulation of CBF, glial activation and inflammation which may contribute to the development of Alzheimer‐like cognitive deficits. Hence, the development of new therapeutic strategies for the treatment of diabetes‐related AD‐like cognitive deficits should take improving autoregulation of CBF into consideration. It is our view that combination therapies that address the accompanying microvascular disease and use drugs to provide strict control of diabetes may potentiate the efficacy of the γ‐secretase inhibitors and anti‐β‐amyloid immunotherapy for the treatment of AD.

Support or Funding Information

This study was supported by grants HL36279 (RJR) and DK104184 (RJR), AG050049 (FF), P20GM104357 (RJR, FF and JMW) and P30 GM103328 (RJR and GKR) from the National Institutes of Health; 16GRNT31200036 (FF) and 12SDG9440034 (JMW) from the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.