Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

Thomas, Riya; Zuchowska, Paulina; Morris, Alan; Marottoli, Felecia M.; Sunny, Sangeeta; Deaton, Ryan; Gann, Peter H.; Tai, Leon M.

doi:10.1186/s40478-016-0387-3

Cited by 50 publications

(109 citation statements)

References 64 publications

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“…Total vessel coverage is an indication of a disrupted cerebrovasculature, and at 8 months of age, we have observed lower vessel coverage in the subiculum and deep layer cortex of female E4FAD+ mice compared to age-matched males (Thomas et al., 2016). The region-specific lowering of vessel coverage is likely driven by the accumulation of Aβ in those regions of EFAD+ mice and increased susceptibility of vessels to damage (see “Discussion” section).…”

Section: Resultsmentioning

confidence: 64%

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

et al. 2017

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Cerebrovascular dysfunction is rapidly reemerging as a major process of Alzheimer’s disease (AD). It is, therefore, crucial to delineate the roles of AD risk factors in cerebrovascular dysfunction. While apolipoprotein E4 (APOE4), Amyloid-β (Aβ), and peripheral inflammation independently induce cerebrovascular damage, their collective effects remain to be elucidated. The goal of this study was to determine the interactive effect of APOE4, Aβ, and chronic repeated peripheral inflammation on cerebrovascular and cognitive dysfunction in vivo. EFAD mice are a well-characterized mouse model that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce human Aβ42 via expression of 5 Familial Alzheimer’s disease (5xFAD) mutations. Here, we utilized EFAD carriers [5xFAD+/−/APOE+/+ (EFAD+)] and noncarriers [5xFAD−/−/APOE+/+ (EFAD−)] to compare the effects of peripheral inflammation in the presence or absence of human Aβ overproduction. Low-level, chronic repeated peripheral inflammation was induced in EFAD mice via systemic administration of lipopolysaccharide (LPS; 0.5 mg/kg/wk i.p.) from 4 to 6 months of age. In E4FAD+ mice, peripheral inflammation caused cognitive deficits and lowered post-synaptic protein levels. Importantly, cerebrovascular deficits were observed in LPS-challenged E4FAD+ mice, including cerebrovascular leakiness, lower vessel coverage, and cerebral amyloid angiopathy-like Aβ deposition. Thus, APOE4, Aβ, and peripheral inflammation interact to induce cerebrovascular damage and cognitive deficits.

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Section: Resultsmentioning

confidence: 64%

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

et al. 2017

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“…Previous data support that APOE4 is associated with higher cerebrovascular leakiness in vivo [32, 33], however the effect of sex is unknown. Further, we have demonstrated that there is higher cerebrovascular leakiness in the cortex, but not the cerebellum of EFAD + F mice at eight-months of age [31]. The higher cerebrovascular leakiness in the cortex may be related to Aβ deposition in EFAD+ mice, or increased susceptibility to age-related vascular deficits.…”

Section: Resultsmentioning

confidence: 67%

“…However, and although not ideal, we can compare our previous data in EFAD+ mice [31] to data obtained in EFAD- mice in this study. This comparison supports that Aβ exacerbates the cognitive decline in female mice that express APOE4.…”

Section: Discussionmentioning

confidence: 84%

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Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

Thomas

Morris

Tai

2017

Heliyon

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Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer’s disease (AD). Two important risk factors for cerebrovascular dysfunction are APOE and female sex, which are primarily researched in the context of high amyloid-β (Aβ) levels as found in AD. However, APOE4 and sex modulate Aβ-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Aβ-independent models that incorporate APOE4 and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express APOE4 and overproduce Aβ, without affecting Aβ levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Aβ-independent cerebrovascular dysfunction. In eight-month old mice that express human APOE, the interaction of APOE4 and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4. Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk.

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“…A previous study has also reported up-regulation of VEGFR-1 in patients with the AD (39), confirming the altered pattern of VEGFR expression in the AD brain. Studies in AD mouse models have shown that treatment with exogenous VEGF can ameliorate memory impairment (40,41) and cerebrovascular deficits both in vivo (42) and in vitro (43), suggesting that engagement of the VEGFR signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells

Angom¹,

Wang²,

Wang³

et al. 2018

FASEB j.

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Aggregated amyloid β (Aβ) peptides in the Alzheimer's disease (AD) brain are hypothesized to trigger several downstream pathologies, including cerebrovascular dysfunction. Previous studies have shown that Aβ peptides can have antiangiogenic properties, which may contribute to vascular dysfunction in the early stages of the disease process. We have generated data showing that brain endothelial cells (ECs) exposed to toxic Aβ1‐42 oligomers can readily enter a senescence phenotype. To determine the effect of Aβ oligomers on brain ECs, we treated early passaged human brain microvascular ECs and HUVECs with high MW Aβ1‐42 oligomers (5 µM, for 72 h). For controls, we used no peptide treatment, 5 µM Aβ1‐42 monomers, and 5 µM Aβ1‐42 fibrils, respectively. Brain ECs treated with Aβ1‐42 oligomers showed increased senescence‐associated β‐galactosidase staining and increased senescence‐associated p21/ p53 expression. Treatment with either Aβ1‐42 monomer or Aβ1‐42 fibrils did not induce senescence in this assay. We then measured vascular endothelial growth factor receptor (VEGFR) expression in the Aβ1‐42 oligomer‐treated ECs, and these cells showed significantly increased VEGFR‐1 expression and decreased VEGFR‐2 levels. Overexpression of VEGFR‐1 in brain ECs readily induced senescence, suggesting a direct role of VEGFR‐1 signaling events in this paradigm. More importantly, small interfering RNA‐mediated knockdown of VEGFR‐1 expression in brain ECs was able to prevent up‐regulation of p21 protein expression and significantly reduced induction of senescence following Aβ1‐42 oligomer treatment. Our studies show that exposure to Aβ1‐42 oligomers may impair vascular functions by altering VEGFR‐1 expression and causing ECs to enter a senescent phenotype. Altered VEGFR expression has been documented in brains of AD patients and suggests that this pathway may play a role in AD disease pathogenesis. These studies suggest that modulating VEGFR‐1 expression and signaling events could potentially prevent senescence and rejuvenate EC functions, and provides us with a novel target to pursue for prevention and treatment of cerebrovascular dysfunction in AD.—Angom, R. S., Wang, Y., Wang, E., Pal, K., Bhattacharya, S., Watzlawik, J. O., Rosenberry, T. L., Das, P., Mukhopadhyay, D. VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells. FASEB J. 33, 4626–4637 (2019). http://www.fasebj.org

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Epidermal growth factor prevents APOE4 and amyloid-beta-induced cognitive and cerebrovascular deficits in female mice

Cited by 50 publications

References 64 publications

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

Peripheral Inflammation,Apolipoprotein E4, and Amyloid-β Interact to Induce Cognitive and Cerebrovascular Dysfunction

Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

VEGF receptor‐1 modulates amyloid β 1–42 oligomer‐induced senescence in brain endothelial cells

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