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 Aβ accumulation and toxic tau phosphorylation in AD animals post-
stroke.