O4-07-02: A novel mouse model of intraneuronal oligomers and congophilic amyloid angiopathy

In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

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Kinetics of Cerebral Amyloid Angiopathy Progression in a Transgenic Mouse Model of Alzheimer Disease

Journal of Neuroscience ◽

10.1523/jneurosci.3854-05.2006 ◽

2006 ◽

Vol 26 (2) ◽

pp. 365-371 ◽

Cited By ~ 48

Author(s):

E. M. Robbins

Keyword(s):

Alzheimer Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Cerebral Amyloid Angiopathy ◽

Transgenic Mouse Model ◽

Amyloid Angiopathy ◽

Cerebral Amyloid ◽

Kinetics Of

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The Innate Immune System in Alzheimer’s Disease

International Journal of Cell Biology ◽

10.1155/2013/576383 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 34

Author(s):

Allal Boutajangout ◽

Thomas Wisniewski

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune System ◽

Innate Immune System ◽

Late Onset ◽

Innate Immune ◽

Amyloid Angiopathy ◽

Functional Variant ◽

The Central Nervous System ◽

Congophilic Amyloid Angiopathy

Alzheimer’s disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloidβ(Aβ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

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High‐Fat‐Diet Intake Enhances Cerebral Amyloid Angiopathy and Cognitive Impairment in a Mouse Model of Alzheimer's Disease, Independently of Metabolic Disorders

Journal of the American Heart Association ◽

10.1161/jaha.115.003154 ◽

2016 ◽

Vol 5 (6) ◽

Cited By ~ 28

Author(s):

Bowen Lin ◽

Yu Hasegawa ◽

Koki Takane ◽

Nobutaka Koibuchi ◽

Cheng Cao ◽

...

Keyword(s):

Cognitive Impairment ◽

Mouse Model ◽

Cerebral Amyloid Angiopathy ◽

High Fat Diet ◽

Metabolic Disorders ◽

Amyloid Angiopathy ◽

High Fat ◽

Model Of Alzheimer’S Disease ◽

Cerebral Amyloid ◽

Diet Intake

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Abstract WP397: Longitudinal Sex Differences in Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.51.suppl_1.wp397 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Michael Maniskas ◽

Jacob Hudobenko ◽

Akhiko Urayama ◽

Louise McCullough ◽

Bharti Manwani

Keyword(s):

Mouse Model ◽

Cerebral Amyloid Angiopathy ◽

Cognitive Deficits ◽

Elderly Women ◽

Amyloid Plaque ◽

Amyloid Angiopathy ◽

Female Mice ◽

Plaque Deposition ◽

Significant Difference ◽

Cerebral Amyloid

Background: Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage in the aging population. It is mostly a consequence of amyloid beta40 (Aβ40) deposition within the cerebral blood vessels. A recent study has shown that this amyloid plaque deposition is more prevalent in the brain of elderly women compared to men. The increase in amyloid plaque deposition is linked to increased cerebral microbleeds (CMBs) and reduced cognition. The major objective of this study to discern if a sexual dichotomy existed in CMBs and cognition using mouse model of CAA. Methods: We used the Tg-SwDI mouse (“CAA mouse”, harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein) model that develops Aβ deposits and cognitive deficits at 3-4 months. Cognitive deficits were analyzed using Fear Conditioning (FC) in pre-symptomatic (3 month) and (12 month) old male and female mice. Briefly, mice were acclimated to the FC chamber for a 2 minute training trial to record baseline. After 1 hour rest, mice were placed back in the chamber for 2 minutes, where they received a 2 millisecond shock (1,000 u/amp). Day 2, activity was recorded for 3 minutes and this measure was compared to baseline to determine Mean Inactive State (MIS-seconds). Mice were euthanized following FC, and brains scanned ex vivo using a MRI T2 Star sequence to assess for CMBs. Results: FC showed a significant difference in MIS (p<0.05) between male (3 and 12 months old) and female (3 months only) mice, n=6/group, suggesting that aged females had significantly lower MIS (Figure 1). MRI showed that aged female mice had more CMBs compared to aged male mice (females, 15.3±7 vs. males 0.25 ±0.2, n= 3/group, p=0.05. Conclusion: In a mouse model of CAA, our results demonstrate that aged females have increased CMBs as compared to males, which may be contributing to decreased cognition as seen on FC. Ongoing studies are designed to further understand the etiology of this sex difference.

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