Reduced Levels of Cerebrospinal Fluid/Plasma Aβ40 as an Early Biomarker for Cerebral Amyloid Angiopathy in RTg-DI Rats

Abstract

The accumulation of fibrillar amyloid β-protein (Aβ) in blood vessels of the brain, the condition known as cerebral amyloid angiopathy (CAA), is a common small vessel disease that promotes cognitive impairment and is strongly associated with Alzheimer’s disease. Presently, the clinical diagnosis of this condition relies on neuroimaging markers largely associated with cerebral macro/microbleeds. However, these are markers of late-stage disease detected after extensive cerebral vascular amyloid accumulation has become chronic. Recently, we generated a novel transgenic rat model of CAA (rTg-DI) that recapitulates multiple aspects of human CAA disease with the progressive accumulation of cerebral vascular amyloid, largely composed of Aβ40, and the consistent emergence of subsequent microbleeds. Here, we investigated the levels of Aβ40 in the cerebrospinal fluid (CSF) and plasma of rTg-DI rats as CAA progressed from inception to late stage disease. The levels of Aβ40 in CSF and plasma precipitously dropped at the early onset of CAA accumulation at three months of age and continued to decrease with the progression of disease. Notably, the reduction in CSF/plasma Aβ40 levels preceded the emergence of cerebral microbleeds, which first occurred at about six months of age, as detected by in vivo magnetic resonance imaging and histological staining of brain tissue. These findings support the concept that reduced CSF/plasma levels of Aβ40 could serve as a biomarker for early stage CAA disease prior to the onset of cerebral microbleeds for future therapeutic intervention.

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

“…Consistent with these previous findings, thalamic hemosiderin deposits in the present cohort are shown in Figure S3a, c. The thalamic region of rTg-DI rats also exclusively exhibit numerous calcified, occluded microvessels and capillaries (Davis et al, 2018;Lee et al, 2020;Zhu, Hatfield, et al, 2020). Figure S3b, d show that these thalamic-calcified occluded vessels are similarly observed in the present cohort of rTg-DI rats.…”

“…Data points show the results from each rat and the group mean ± SD of n = 6 rTg-DI rats all three brain regions the presence of thrombotic events is largely restricted to the thalamic region of rTg-DI rats (Davis et al, 2018;Lee et al, 2020;Zhu, Hatfield, et al, 2020;. For example, at 12 M, microbleeds are prominently observed bilaterally in the thalamic region based on magnetic resonance imaging and histological staining for hemosiderin (Davis et al, 2018;Lee et al, 2020;Zhu, Hatfield, et al, 2020;. Consistent with these previous findings, thalamic hemosiderin deposits in the present cohort are shown in Figure S3a, c.…”

“…Although rTg-DI rats develop consistent early-onset and extensive microvascular CAA, parenchymal fibrillar amyloid plaques and larger vessel CAA type-2 are largely absent. In this model, microvascular CAA is accompanied by extensive perivascular neuroinflammation, degeneration and loss of capillary pericytes, cerebral microbleeds, microvessel occlusions, loss of axonal integrity, and white matter degeneration (Davis et al, 2018;Lee et al, 2020;. Further, rTg-DI rats develop a 'cognitive slowing' phenotype (Popescu et al, 2020) that is similar to the deteriorating executive function observed in human CAA (Case et al, 2016;Planton et al, 2017).…”

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

“…To investigate potentially different subtypes of microglia in rTg-DI rats, we performed double immunolabeling for Iba-1, a common resident microglial marker, and OX6 MHCII a marker that has been used to identify activated macrophagic microglia [22,23]. In 3 and 12-month wildtype rats, the small number of microglia were labeled exclusively with Iba-1 and exhibited their resting state morphology (Additional Fig.…”

“…These findings suggest that rTg-DI rats have the potential to be a useful preclinical platform to study the pathogenesis of CAA type-1, to identify biomarkers for disease and to test therapeutic interventions. Indeed, we recently showed that decreasing levels of Aβ40 peptide in cerebrospinal fluid correlated with the progression of CAA in this model [22]. To better understand the utility of rTg-DI rats as a valid preclinical model, here we investigated the temporal development of several perivascular pathologies that are commonly observed with human CAA type-1.…”