Interplay Between Age, Cerebral Small Vessel Disease, Parenchymal Amyloid-beta, and Tau Pathology: Longitudinal Studies in Hypertensive Stroke-Prone Rats

Background: Accumulation of amyloid-beta (A beta) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer's disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction and blood-brain barrier (BBB) breakdown. Objective: We test the hypothesis that characteristic features of CSVD are associated with the accumulation of A beta and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP). Methods: Amyloid-beta protein precursor (A beta PP) and tau were investigated by western blotting (n = 12 SHRSP, age 20 weeks). Lectin staining and plasma protein immunocytochemistry for BBB examination were performed in 38 SHRSP (age 12-44 weeks) and A beta (n = 29) and ptau (n = 17) immunocytochemistry in 20-44 week-old SHRSP. We assessed the correlation between extracellular amyloid deposits and features of CSVD (n = 135, 12-44 weeks). Results: In 20 week-old SHRSP, cortical A beta PP expression was significantly increased compared to Wistar controls but tau levels were unchanged. At ages of 20-44 weeks, SHRSP exhibited an age-dependent increase in extracellular A beta. Ptau was observed in 26-44 week-old SHRSP. Distinct features of CSVD pathology developed from the age of 12 weeks on. Conclusion: We demonstrate that in a hypertensive rat model that displays features of CSVD from 12 weeks, there is an age-dependent extracellular deposition of A beta observed from 20 weeks onwards, increased A beta PP expression at 20 weeks and ptau accumulation from 26 weeks on. This study suggests that CSVD associated with hypertension results in an age-related failure of A beta clearance, increase in A beta PP expression, and intraneuronal tau hyperphosphorylation.