Background: Cerebral amyloid angiopathy (CAA) is common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a transgenic rat model of capillary CAA type-1 that develops many pathological features of human disease. However, a complementary rat model of larger vessel CAA type-2 disease has been lacking.
Methods: A novel transgenic rat model (rTg-D) was generated that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops larger vessel CAA type-2. Quantitative biochemical and pathological analyses were performed to characterize the progression of CAA and associated pathologies in aging rTg-D rats.
Results: rTg-D rats begin to accumulate Aβ in brain and develop varying levels of larger vessel CAA type-2, in the absence of capillary CAA type-1, starting around 18 months of age. Larger vessel CAA was mainly composed of the Aβ40 peptide and most prominent in surface leptomeningeal/pial vessels and arterioles of the cortex and thalamus. Cerebral microbleeds and small vessel occlusions were present mostly in the thalamic region of affected rTg-D rats. In contrast to capillary CAA type-1 the amyloid deposited within the walls of larger vessels of rTg-D rats did not promote perivascular astrocyte and microglial responses or accumulate the Aβ chaperone apolipoprotein E.
Conclusion: Although variable in severity, the rTg-D rats specifically develop larger vessel CAA type-2 that reflects many of the pathological features of human disease and provide a new model to investigate the pathogenesis of this condition.
Keywords: AD, Alzheimer's disease; Amyloid β protein; ApoE, Apolipoprotein E; Aβ, Amyloid β-protein; AβPP, Amyloid β-protein precursor; CAA, Cerebral amyloid angiopathy; Cerebral amyloid angiopathy; Dutch mutation; GFAP, Glial fibrillary acidic protein; ICH, Intracerebral hemorrhage; Iba-1, Ionized calcium-binding adapter molecule 1; Microbleed; Small vessel disease; Transgenic rat; VCID, Vascular cognitive impairment and dementia; WT, Wild-type.
© 2022 The Authors. Published by Elsevier B.V.