Neurobiology of Disease Reducing Cerebral Microvascular Amyloid- Protein Deposition Diminishes Regional Neuroinflammation in Vasculotropic Mutant Amyloid Precursor Protein Transgenic Mice

Cerebral microvascular amyloid(A ) protein deposition is emerging as an important contributory factor to neuroinflammation and dementia in Alzheimer’s disease and related familial cerebral amyloid angiopathy disorders. In particular, cerebral microvascular amyloid deposition, but not parenchymal amyloid, is more often correlated with dementia. Recently, we generated transgenic mice (Tg-SwDI) expressing the vasculotropic Dutch (E693Q)/Iowa (D694N) mutant human A precursor protein in brain that accumulate abundant cerebral microvascular fibrillar amyloid deposits. In the present study, our aim was to assess how the presence or absence of fibrillar A deposition in the cerebral microvasculature affects neuroinflammation in Tg-SwDI mice. Using Tg-SwDI mice bred onto an apolipoprotein E gene knock-out background, we found a strong reduction of fibrillar cerebral microvascular A deposition, which was accompanied by a sharp decrease in microvascular-associated neuroinflammatory cells and interleukin-1 levels. Quantitative immunochemical measurements showed that this reduction of the neuroinflammation occurred in the absence of lowering the levels of total A 40/A 42 or soluble A oligomers in brain. These findings suggest that specifically reducing cerebral microvascular fibrillar A deposition, in the absence of lowering either the total amount of A or soluble A oligomers in brain, may be sufficient to ameliorate microvascular amyloid-associated neuroinflammation.