Direct AT2R Stimulation Slows Post-stroke Cognitive Decline in the 5XFAD Alzheimer's Disease Mice

Alzheimer's disease (AD), currently the single leading cause of death still on the rise, almost always coexists alongside vascular cognitive impairment (VCI). In fact, the ischemic disease affects up to 90% of AD patients, with strokes and major infarctions representing over a third of vascular lesions. Studies also confirmed that amyloid plaques, typical of AD, are much more likely to cause dementia if strokes or cerebrovascular damage also exist, leading to the term mixed pathology cognitive impairment. Although its incidence is expected to grow, there are no satisfactory treatments. There is hence an urgent need for safe and effective therapies that preserve cognition, maintain function, and prevent the clinical deterioration that results from the progression of this irreversible, neurodegenerative disease. To our knowledge, this is the first study to investigate the effects of long-term treatment with C21, a novel angiotensin II type 2 receptor (AT2R) agonist, on the development of mixed pathology cognitive impairment. This was accomplished using a unique model that employs the fundamental elements of both AD and VCI. Treatment with C21/vehicle was started 1 h post-stroke and continued for 5 weeks in mice with concurrent AD pathology. Efficacy was established through a series of functional tests assessing various aspects of cognition, including spatial learning, short-term/working memory, long-term/reference memory, and cognitive flexibility, in addition to the molecular markers characteristic of AD. Our findings demonstrate that C21 treatment preserves cognitive function, maintains cerebral blood flow, and reduces A beta accumulation and toxic tau phosphorylation in AD animals post-stroke.

Automated summary

Alzheimer's disease (AD) always coexists with vascular cognitive impairment (VCI), and vascular lesions can worsen the cognitive decline caused by AD. There is currently no satisfactory treatment for this irreversible neurodegenerative disease, emphasizing the need for safe and effective therapies. This study investigated the effects of long-term treatment with C21, an AT2R agonist, on mixed pathology cognitive impairment using a unique mouse model that combines AD and VCI. The results showed that C21 treatment preserved cognitive function, maintained cerebral blood flow, and reduced AD pathology.