epidermal-growth-factor and Cerebrovascular-Disorders

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoprotein E3; Apolipoprotein E4; Brain; Capillary Permeability; Cerebrovascular Disorders; Cognitive Dysfunction; Disease Models, Animal; Epidermal Growth Factor; Female; Humans; Male; Mice, Transgenic; Neuroprotective Agents; Nootropic Agents; Peptide Fragments; Plaque, Amyloid; Sex Characteristics

1. We examined the proliferative rates of cultured astrocytes isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHRSR). Wistar-Kyoto rats (WKY) were used as a control for SHRSP and SHRSR. 2. In the presence of 10% fetal bovine serum (FBS), the doubling time for astrocytes from SHRSP and SHRSR was significantly shorter than WKY. 3. When quiescent astrocytes derived from SHRSP or SHRSR were released from serum-deprivation, the DNA synthesis was stimulated 13.3-fold and 12.5-fold, respectively, whereas only a 7.76-fold increase was observed in WKY astrocytes. 4. Further we studied the effects of two growth factors, epidermal growth factor (EGF) and fibroblast growth factor (FGF) on astrocytes proliferation. EGF induced greater DNA synthesis in SHRSP and SHRSR astrocytes compared with WKY astrocytes, although FGF had little or no effect. 5. Total cholesterol levels in SHRSP astrocytes and SHRSR astrocytes were significantly lower than that of WKY astrocytes, which was consistent with our previous observations in cultured vascular smooth muscle cells. 6. There was no difference in morphology among the cultured astrocytes from the three strains. 7. The abnormality of growth rate and cell membranes composition of astrocytes might be closely related to the genetic phenotypes (acute death of neurons and oedema of astrocytes) of SHRSP or SHRSR.

Topics: Animals; Astrocytes; Cattle; Cell Cycle; Cell Division; Cell Membrane; Cells, Cultured; Cerebrovascular Disorders; Cholesterol; DNA; Epidermal Growth Factor; Fibroblast Growth Factors; Hypertension; Immunohistochemistry; Microscopy, Electron; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Serum Albumin; Thymidine