Memory deficiency, cerebral amyloid angiopathy, and amyloid-β plaques in APP+PS1 double transgenic rat model of Alzheimer’s disease

Abstract

Transgenic rat models of Alzheimer’s disease were used to examine differences in memory and brain histology. Double transgenic female rats (APP+PS1) over-expressing human amyloid precursor protein (APP) and presenilin 1 (PS1) and single transgenic rats (APP21) over-expressing human APP were compared with wild type Fischer rats (WT). The Barnes maze assessed learning and memory and showed that both APP21 and APP+PS1 rats made significantly more errors than the WT rats during the acquisition phase, signifying slower learning. Additionally, the APP+PS1 rats made significantly more errors following a retention interval, indicating impaired memory compared to both the APP21 and WT rats. Immunohistochemistry using an antibody against amyloid-β (Aβ) showed extensive and mostly diffuse Aβ plaques in the hippocampus and dense plaques that contained tau in the cortex of the brains of the APP+PS1 rats. Furthermore, the APP+PS1 rats also showed vascular changes, including cerebral amyloid angiopathy with extensive Aβ deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the Aβ accumulation observed in arterial, venous, and capillary walls, APP+PS1 rats also displayed enlarged blood vessels and perivascular space. Overall, the brain histopathology and behavioral assessment showed that the APP+PS1 rats demonstrated behavioral characteristics and vascular changes similar to those commonly observed in patients with Alzheimer’s disease.

White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer’s disease rat model

“…This is the first demonstration of the impact of hypercaloric diet on white matter in a vulnerable aging brain with increased levels of pathogenic hAPP. These TG rats have been previously characterized to have dense neuronal staining for hAPP, but no evidence of plaques [30,33]. Amyloid-β plaque deposits were also not detected in the TG and comorbid rats in this study.…”

“…The comorbidity of prodromal AD with metabolic syndrome was examined in a novel APP21 transgenic (TG) rat model of pre-AD [30,31] created on a Fischer 344 background which carries a human APP (hAPP) gene with Swedish and Indiana mutations, implicated in early-onset AD. This rat has been previously shown to express high levels of human brain APP and serum β-amyloid (Aβ1-40 and 1-42) without spontaneous Aβ plaques deposition in brain tissue with age [32,33]. Thus, it allows us to study the early interaction between metabolic syndrome and prodromal AD-like processes in the brain in a model with AD-predisposing conditions.…”

Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis

“…One report demonstrated venular amyloid in APP/PS1/Cx3cr1 mice presenting as small, globular Aβ aggregates in veins at 5 months of age and at 9 months of age, along with the presence of the ring-like Aβ deposition in arteries [27]. Michaud and colleagues proposed that the Aβ deposits in veins precede arterial Aβ deposition [27], which is contrary to previous findings [18,37,53,59]. In addition, Michaud and colleagues demonstrated preferential adherence of monocytes to surrounding Aβ-laden veins, but not arteries, and that these monocytes internalize venular amyloid for removal into the bloodstream [27].…”

“…The APP+PS1 rat model, that shows extensive CAA, Aβ plaque formation, and behavioural alterations, demonstrated Aβ deposits in leptomeningeal and cortical arteries, cortical capillaries, as well as severe deposition in the leptomeningeal and cortical veins using immunohistochemical analyses [53]. In addition, there were significant alterations in the veins including enlarged cortical veins and perivascular spaces, and stenosis of collagen, tau, and Aβ [53]. These pathological features have also been identified clinically in venous insufficiency and vasogenic edema, typically depicted as hyperintensities in magnetic resonance imaging (MRI) [30,31,47,52,54,55].…”

“…Currently, in vivo animal studies have observed venular amyloid. The APP+PS1 rat model, that shows extensive CAA, A plaque formation, and behavioural alterations, demonstrated A deposits in leptomeningeal and cortical arteries, cortical capillaries, as well as severe deposition in the leptomeningeal and cortical veins using immunohistochemical analyses [53]. In addition, there were significant alterations in the veins including enlarged cortical veins and perivascular spaces, and stenosis of collagen, tau, and A [53].…”