Interplay between age, cerebral small vessel disease, parenchymal amyloid-β, and tau pathology: longitudinal studies in hypertensive stroke-prone rats.

Background: Accumulation of amyloid-β (Aβ) 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 Aβ and ptau in non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP).

Methods: Amyloid-β protein precursor (AβPP) 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 Aβ (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 AβPP 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 Aβ. 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 Aβ observed from 20 weeks onwards, increased AβPP 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 Aβ clearance, increase in AβPP expression, and intraneuronal tau hyperphosphorylation.