A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy

Abstract

Accumulation of fibrillar amyloid b protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid b protein in brain and faithfully recapitulates many of the pathologic aspects of human smallvessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. (Am J Pathol 2018, 188: 2877e2889; https://doi.

Robust neuroinflammation and perivascular pathology in rTg-DI rats, a novel model of microvascular cerebral amyloid angiopathy

“…In addition, many neuronal cell bodies were now labeled with the axonal marker showing a striking redistribution of this reactivity. These findings suggest that there are indeed marked impacts of advancing CAA pathology on neuronal integrity, which likely contribute to behavioral deficits in rTg-DI rats [16].…”

“…Regarding this latter point, the activation stimulus here involves vascular amyloid and, in rTg-DI rats, involves familial Dutch/Iowa CAA mutant Aβ. Further specifying this pathogenic stimulus, we previously reported that in vascular amyloid, the Aβ peptide adopts a distinct antiparallel fibril configuration [16,50]. Thus, the source and activation state of microglia can be unique for distinct disease states in the CNS and requires further investigation in this model [51].…”

“…Most previous animal studies on CAA involved the use of various human AβPP transgenic mouse models that develop variable levels of CAA in the presence or absence of parenchymal amyloid pathology [41][42][43][44]. Recently, we reported the generation of a novel transgenic rat model (rTg-DI) that robustly develops capillary CAA type-1 [16]. We showed that rTg-DI rats express low amounts of human chimeric Dutch (E22Q)/Iowa (D23N) familial CAA mutant Aβ in the brain and develop early-onset and progressive microvascular CAA.…”

“…The generation of rTg-DI transgenic rats was recently described [16]. These rats modestly express human Swedish/Dutch/Iowa mutant AβPP under the control of the neuronal-specific Thy1.2 promoter.…”

“…Recently, we generated a novel transgenic rat model (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant Aβ in the brain [16]. The rTg-DI rat model shows many pathologic aspects of human small vessel CAA type-1, including similar vascular Aβ structure, glial activation, and microhemorrhages, accompanied by behavioral deficits [16]. In order to gain a better understanding of the mechanisms underlying CAA pathology, we investigated perivascular pathological processes that accompany CAA type-1 in the rTg-DI rat model.…”