Longitudinal Cognitive Decline in a Novel Rodent Model of Cerebral Amyloid Angiopathy Type-1.

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by beta-amyloid (A beta) accumulation in and around the cerebral blood vessels and capillaries and is highly comorbid with Alzheimer's disease (AD). Familial forms of CAA result from mutations within the A beta domain of the amyloid beta precursor protein (A beta PP). Numerous transgenic mouse models have been generated around expression of human A beta PP mutants and used to study cerebral amyloid pathologies. While behavioral deficits have been observed in many A beta PP transgenic mouse lines, relative to rats, mice are limited in behavioral expression within specific cognitive domains. Recently, we generated a novel rat model, rTg-DI, which expresses Dutch/Iowa familial CAA A beta in brain, develops progressive and robust accumulation of cerebral microvascular fibrillar A beta beginning at 3 months, and mimics many pathological features of the human disease. The novel rTg-DI model provides a unique opportunity to evaluate the severity and forms of cognitive deficits that develop over the emergence and progression of CAA pathology. Here, we present an in-depth, longitudinal study aimed to complete a comprehensive assessment detailing phenotypic disease expression through extensive and sophisticated operant testing. Cohorts of rTg-DI and wild-type (WT) rats underwent operant testing from 6 to 12 months of age. Non-operant behavior was assessed prior to operant training at 4 months and after completion of training at 12 months. By 6 months, rTg-DI animals demonstrated speed-accuracy tradeoffs that later manifested across multiple operant tasks. rTg-DI animals also demonstrated delayed reaction times beginning at 7 months. Although non-operant assessments at 4 and 12 months indicated comparable mobility and balance, rTg-DI showed evidence of slowed environmental interaction. Overall, this suggests a form of sensorimotor slowing is the likely core functional impairment in rTg-DI rats and reflects similar deficits observed in human CAA.