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Memory deficiency, cerebral amyloid angiopathy, and amyloid-? 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-? (A?) showed extensive and mostly diffuse A? 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 A? deposits in cortical and leptomeningeal blood vessel walls and venous collagenosis. In addition to the A? 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.

SUBMITTER: Klakotskaia D

PROVIDER: S-EPMC5895023 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Klakotskaia Diana D Agca Cansu C Richardson Rachel A RA Stopa Edward G EG Schachtman Todd R TR Agca Yuksel Y

PloS one 20180411 4

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 ...[more]

PMID: 29641600

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Project description:BackgroundAlzheimer's disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice.MethodsAPP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior.ResultsIn APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed.ConclusionsApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

Project description:Cerebral amyloid angiopathy (CAA), a common comorbidity of Alzheimer's disease (AD), is a cerebral small vessel disease (CSVD) characterized by deposition of fibrillar amyloid β (Aβ) in blood vessels of the brain and promotes neuroinflammation and vascular cognitive impairment and dementia (VCID). Hypertension, a prominent non-amyloidal CSVD, has been found to increase risk of dementia, but clinical data regarding its effects in CAA patients is controversial. To understand the effects of hypertension on CAA, we bred rTg-DI transgenic rats, a model of CAA, with spontaneously hypertensive, stroke prone (SHR-SP) rats producing bigenic rTg-DI/SHR-SP and non-transgenic SHR-SP littermates. At 7 months (M) of age, cohorts of both rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic blood pressures. However, transgene human amyloid β-protein (Aβ) precursor and Aβ peptide levels, as well as behavioral testing showed no changes between bigenic rTg-DI/SHR-SP and rTg-DI rats. Subsequent cohorts of rats were aged further to 10 M where bigenic rTg-DI/SHR-SP and SHR-SP littermates exhibit elevated systolic and diastolic blood pressures. Vascular amyloid load in hippocampus and thalamus was significantly decreased, whereas pial surface vessel amyloid increased, in bigenic rTg-DI/SHR-SP rats compared to rTg-DI rats suggesting a redistribution of vascular amyloid in bigenic animals. There was activation of both astrocytes and microglia in rTg-DI rats and bigenic rTg-DI/SHR-SP rats not observed in SHR-SP rats indicating that glial activation was likely in response to the presence of vascular amyloid. Thalamic microbleeds were present in both rTg-DI rats and bigenic rTg-DI/SHR-SP rats. Although the number of thalamic small vessel occlusions were not different between rTg-DI and bigenic rTg-DI/SHR-SP rats, a significant difference in occlusion size and distribution in the thalamus was found. Proteomic analysis of cortical tissue indicated that bigenic rTg-DI/SHR-SP rats largely adopt features of the rTg-DI rats with enhancement of certain changes. Our findings indicate that at 10 M of age non-pharmacological hypertension in rTg-DI rats causes a redistribution of vascular amyloid and significantly alters the size and distribution of thalamic occluded vessels. In addition, our findings indicate that bigenic rTg-DI/SHR-SP rats provide a non-pharmacological model to further study hypertension and CAA as co-morbidities for CSVD and VCID.

Project description:Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.

Dataset Information

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

Publications

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

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