Cerebrovascular accumulation of the amyloid ?-protein (A?), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related familial CAA disorders. There is substantial evidence that neuronally-derived A? peptides normally migrate to the cerebral microvasculature where they are cleared from the CNS by transport across the capillary blood-brain barrier into the circulation. Familial forms of CAA involve the early and severe cerebrovascular accumulation of A? peptides with specific mutations such as the Dutch mutant E22Q and Iowa mutant D23N. However, in familial forms of CAA generally only one mutant A?PP allele is present indicating that the pool A? peptides in brain is a mixture of wild-type and CAA mutant forms. How wild-type and CAA mutant A? peptides interact in vivo to affect clearance and produce CAA pathology is not understood. Recently, we generated a transgenic mouse model that produces Dutch/Iowa CAA mutant A? peptides in brain (Tg-SwDI) and develops cerebral microvascular amyloid with associated neuroinflammation and behavioral deficits. The Tg-SwDI mouse has provided an invaluable model to study the genesis and consequences of familial microvascular CAA. However, the amyloid pathology of Tg-SwDI mice is the result of only human Dutch/Iowa CAA mutant A? peptides. The impact of human CAA mutant A? peptides on the accumulation and clearance of human wild-type A? peptides in this model is unknown. Thus, we hypothesize in this proposal that human CAA mutant A? and human wild-type A? peptides interact in the CNS to influence clearance and cerebrovascular accumulation of A? in transgenic mice. To test our hypothesis we will take the experimental approach of crossing the base Tg-SwDI mice with two different transgenic models that produce either 1) elevated levels of human wild-type A? peptides in brain and develop abundant amyloid pathology or 2) low, physiological levels of human wild-type Ass peptides in brain with no amyloid pathology. Then we will evaluate the effects on development of CAA, CNS A? peptide efflux into the circulation, and the downstream neuroinflammation and behavioral deficits associated with CAA. Completion of the above goals will provide new and significant information regarding how wild- type and CAA mutant A? peptides interact in vivo in the brain. These studies will provide useful insight into understanding mechanisms involved in A? clearance and pathological accumulation at the cerebral vasculature, particularly in familial forms of CAA, and may lead to new avenues for approaches to impede the initiation and progression of CAA and/or facilitate A? efflux from the CNS.
Accumulation of a protein fragment, known as amyloid ? -protein (A?), in the brain is a key pathological feature of Alzheimer's disease and related disorders. Mutations have been identified in A? that cause it to accumulate in brain more severely than normal A?. The purpose of this proposal is to investigate how mutant A? interacts with normal A? to increase its accumulation in brain.
| Xu, Wenjin; Xu, Feng; Anderson, Maria E et al. (2014) Cerebral microvascular rather than parenchymal amyloid-? protein pathology promotes early cognitive impairment in transgenic mice. J Alzheimers Dis 38:621-32 |
| Xu, Feng; Kotarba, AnnMarie E; Ou-Yang, Ming-Hsuan et al. (2014) Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice. J Biol Chem 289:17895-908 |
