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

ABSTRACT: 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-? (A?) levels as found in AD. However, APOE4 and sex modulate A?-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in A?-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 A?, without affecting A? 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 A?-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.

SUBMITTER: Thomas R

PROVIDER: S-EPMC5463012 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Thomas Riya R Morris Alan W J AWJ Tai Leon M LM

Heliyon 20170607 6

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 f ...[more]

PMID: 28626809

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Project description:APOE4 is a major genetic risk factor for Alzheimer's disease and high amyloid-? (A?) levels in the brain are a pathological hallmark of the disease. However, the contribution of specific APOE-modulated A?-dependent and A?-independent functions to cognitive decline remain unclear. Increasing evidence supports a role of APOE in modulating cerebrovascular function, however whether ameliorating this dysfunction can improve behavioral function is still under debate. We have previously demonstrated that systemic epidermal growth factor (EGF) treatment, which is important for vascular function, at early stages of pathology (treatment from 6 to 8 months) is beneficial for recognition and spatial memory and cerebrovascular function in female mice that express APOE4. These data raise the important question of whether EGF can improve APOE4-associated cerebrovascular and behavioral dysfunction when treatment is initiated at an age of advanced pathology. Positive findings would support the development of therapies that target cerebrovascular dysfunction associated with APOE4 in aging and AD in individuals with advanced cognitive impairment. Therefore, in this study female mice that express APOE4 in the absence (E4FAD- mice) or presence (E4FAD+ mice) of A? overproduction were treated from 8 to 10 months of age systemically with EGF. EGF treatment mitigated behavioral dysfunction in recognition memory and spatial learning and improved hippocampal neuronal function in both E4FAD+ and E4FAD- mice, suggesting that EGF treatment improves A?-independent APOE4-associated deficits. The beneficial effects of EGF treatment on behavior occurred in tandem with improved markers of cerebrovascular function, including lower levels of fibrinogen, lower permeability when assessed by MRI and higher percent area coverage of laminin and CD31 in the hippocampus. These data suggest a mechanistic link among EGF signaling, cerebrovascular function and APOE4-associated behavioral deficits in mice with advanced AD-relevant pathology.

Project description:IntroductionWomen who carry a BRCA1 mutation typically develop "triple-negative" breast cancers (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor and Her2/neu. In contrast to ER-positive tumors, TNBCs frequently express high levels of epidermal growth factor receptor (EGFR). Previously, we found a disproportionate fraction of progenitor cells in BRCA1 mutation carriers with EGFR overexpression. Here we examine the role of EGFR in mammary epithelial cells (MECs) in the emergence of BRCA1-related tumors and as a potential target for the prevention of TNBC.MethodsCultures of MECs were used to examine EGFR protein levels and promoter activity in response to BRCA1 suppression with inhibitory RNA. EGFR was assessed by immunoblot and immunofluorescence analysis, real-time reverse transcriptase-polymerase chain reaction assay (RT-PCR) and flow cytometry. Binding of epidermal growth factor (EGF) to subpopulations of MECs was examined by Scatchard analysis. The responsiveness of MECs to the EGFR inhibitor erlotinib was assessed in vitro in three-dimensional cultures and in vivo. Mouse mammary tumor virus-Cre recombinase (MMTV-Cre) BRCA1flox/flox p53?/? mice were treated daily with erlotinib or vehicle control, and breast cancer-free survival was analyzed using the Kaplan-Meier method.ResultsInhibition of BRCA1 in MECs led to upregulation of EGFR with an inverse correlation of BRCA1 with cellular EGFR protein levels (r² = 0.87) and to an increase in cell surface-expressed EGFR. EGFR upregulation in response to BRCA1 suppression was mediated by transcriptional and posttranslational mechanisms. Aldehyde dehydrogenase 1 (ALDH1)-positive MECs expressed higher levels of EGFR than ALDH1-negative MECs and were expanded two- to threefold in the BRCA1-inhibited MEC population. All MECs were exquisitely sensitive to EGFR inhibition with erlotinib in vitro. EGFR inhibition in MMTV-Cre BRCA1flox/flox p53?/? female mice starting at age 3 months increased disease-free survival from 256 days in the controls to 365 days in the erlotinib-treated cohort.ConclusionsWe propose that even partial loss of BRCA1 leads to an overall increase in EGFR expression in MECs and to an expansion of the highly EGFR-expressing, ALDH1-positive fraction. Increased EGFR expression may confer a growth advantage to MECs with loss of BRCA1 at the earliest stages of transformation. Employing EGFR inhibition with erlotinib specifically at this premalignant stage was effective in decreasing the incidence of ER-negative breast tumors in this mouse model.

Dataset Information

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

Publications

Epidermal growth factor prevents <i>APOE4</i>-induced cognitive and cerebrovascular deficits in female mice.

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