Transgenic rat models for cerebral amyloid angiopathy type‐1 and ‐2 and related vascular cognitive impairment and dementia (VCID)

Abstract

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease commonly found in the elderly population and in patients with Alzheimer's disease and is significant driver of vascular cognitive impairment and dementia (VCID). CAA exists in two forms: type-1 which affects small microvessels and capillaries and type-2 which primarily affects small arteries and arterioles. Our understanding of how these different forms of CAA promote VCID is hampered by reliable preclinical models. Recently, we generated novel transgenic rat models of CAA type-1 and CAA type-2 to investigate the development and pathological consequences of each type of CAA and their impact on VCID. Cohorts of CAA type-1 and CAA type-2 transgenic rats and wild-type rats were aged from three to twenty four months of age. Magnetic resonance imaging (MRI) was performed to determine the effects of progressive CAA pathology on white matter changes and emergence of cerebral microbleeds. Quantitative histological analyses were performed to measure progressive severity of CAA, neuroinflammation and cerebral microbleeds. A battery of behavioral task assessments was performed to reveal the impact of CAA on cognitive performance. CAA type-1 rats developed microvascular CAA starting at ≈3 months of age that became severe at 12 months leading to a moribund state. CAA type-2 rats developed CAA pathology later starting ≈12 months of age and progressed to 24 months. Histological analysis showed CAA type-1 rats exhibited early-onset perivascular neuroinflammation and microvascular pathology including capillary occlusions and microbleeds. In contrast, CAA type-2 rats presented little evidence of perivascular neuroinflammation and less extensive microbleeds. MR imaging showed that CAA type-1 rats presented with white matter loss at ≈6 months of age. Behavioral analysis revealed that CAA type-1 rats displayed a distinct form sensorimotor slowing that was not observed in CAA type-2 rats. CAA type-1 rats recapitulate many of the pathological features of human microvascular CAA including perivascular neuroinflammation and white matter loss and exhibit cognitive changes. In contrast, CAA type-2 rats lack these particular pathological features and did not display cognitive changes. These findings suggest that CAA-associated neuroinflammation and white matter loss may play an important role in VCID.