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

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Thomas, Riya, Zuchowska, Paulina, Morris, Alan W. J., Marottoli, Felecia M., Sunny, Sangeeta, Deaton, Ryan, Gann, Peter H., Tai, Leon M.·2016·Acta Neuropathologica Communications
DOI 10.1186/s40478-016-0387-3PMC PMC5084423
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Abstract

Cerebrovascular (CV) dysfunction is emerging as a critical component of Alzheimer's disease (AD), including altered CV coverage. Angiogenic growth factors (AGFs) are key for controlling CV coverage, especially during disease pathology. Therefore, evaluating the effects of AGFs in vivo can provide important information on the role of CV coverage in AD. We recently demonstrated that epidermal growth factor (EGF) prevents amyloid-beta (Aβ)-induced damage to brain endothelial cells in vitro. Here, our goal was to assess the protective effects of EGF on cognition, CV coverage and Aβ levels using an AD-Tg model that incorporates CV relevant AD risk factors. APOE4 is the greatest genetic risk factor for sporadic AD especially in women and is associated with CV dysfunction. EFAD mice express human APOE3 (E3FAD) or APOE4 (E4FAD), overproduce human Aβ42 and are a well characterized model of APOE pathology. Thus, initially the role of APOE and sex in cognitive and CV dysfunction was assessed in EFAD mice in order to identify a group for EGF treatment. At 8 months E4FAD female mice were cognitively impaired, had low CV coverage, high microbleeds and low plasma EGF levels. Therefore, E4FAD female mice were selected for an EGF prevention paradigm (300 μg/kg/wk, 6 to 8.5 months). EGF prevented cognitive decline and was associated with lower microbleeds and higher CV coverage, but not changes in Aβ levels. Collectively, these data suggest that EGF can prevent Aβ-induced damage to the CV. Developing therapeutic strategies based on AGFs may be particularly efficacious for APOE4-induced AD risk.

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  • Previous reports have demonstrated that gender can affect AD pathology, microglia response and APOE expression, while the protective and disease causing effects of APOE2 and APOE4 are variable in different ethnic populations.

    “Previous reports have demonstrated that gender can affect AD pathology, microglia response and APOE expression (Stephen et al, 2019; Thomas et al, 2016; Sala Frigerio et al, 2019), while the protective and disease causing effects of APOE2 and APOE4 are variable in different ethnic populations (Farrer et al, 1997; Naslavsky et al, 2022).”

    From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Thomas et al, 2016

    The Introduction and the Discussion section on sex and APOE4-induced dysfunction report greater APOE4-associated AD risk in females and sex-related differences in AD-like pathology. The Discussion mentions microglial inflammatory responses and suggests females may have a stronger brain inflammatory response, but does not establish a sex-specific microglial response or a sex effect on APOE expression. The ethnicity clause is attributed to other citations, not Thomas et al.; the indexed passages have no page numbers. (LLM, conf=0.85)

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Authors
Thomas, R., Zuchowska, P., Morris, A. W. J., Marottoli, F. M., Sunny, S., Deaton, R., Gann, P. H., & Tai, L. M.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Tai, Leon M.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2016-10-27
Volume
4
Issue
1
Pages
111-111
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-016-0387-3
PMC
PMC5084423
OpenAlex
W2543324357
Cited by
72
References
9
Citations by year
2026: 7 · 2025: 8 · 2024: 14 · 2023: 11 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 3 · 2017: 6
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
epidermal growth factor, APOE ε4, amyloid-beta, Alzheimer's disease, cerebrovascular dysfunction, angiogenic factors, cognitive decline, cerebral microbleeds, sex differences, female mice, brain endothelial cells
MeSH terms
Alzheimer Disease, Animals, Brain, Capillary Permeability, Cerebrovascular Disorders, Disease Models, Animal, Epidermal Growth Factor, Female, Humans, Male, Mice, Transgenic, Peptide Fragments, Sex Characteristics, Amyloid beta-Peptides, Neuroprotective Agents, Nootropic Agents, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid, Cognitive Dysfunction

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