title: Pharmacological modulation of dietary lipid-induced cerebral capillary dysfunction: Considerations for reducing risk for Alzheimer's disease.
abstract: An increasing body of evidence suggests that cerebrovascular dysfunction and microvessel disease precede the evolution of hallmark pathological features that characterise Alzheimer's disease (AD), consistent with a causal association for onset or progression. Recent studies, principally in genetically unmanipulated animal models, suggest that chronic ingestion of diets enriched in saturated fats and cholesterol may compromise blood-brain barrier (BBB) integrity resulting in inappropriate blood-to-brain extravasation of plasma proteins, including lipid macromolecules that may be enriched in amyloid-β (Aβ). Brain parenchymal retention of blood proteins and lipoprotein bound Aβ is associated with heightened neurovascular inflammation, altered redox homeostasis and nitric oxide (NO) metabolism. Therefore, it is a reasonable proposition that lipid-lowering agents may positively modulate BBB integrity and by extension attenuate risk or progression of AD. In addition to their robust lipid lowering properties, reported beneficial effects of lipid-lowering agents were attributed to their pleiotropic properties via modulation of inflammation, oxidative stress, NO and Aβ metabolism. The review is a contemporary consideration of a complex body of literature intended to synthesise focussed consideration of mechanisms central to regulation of BBB function and integrity. Emphasis is given to dietary fat driven significant epidemiological evidence consistent with heightened risk amongst populations consuming greater amounts of saturated fats and cholesterol. In addition, potential neurovascular benefits associated with the use of hypolipidemic statins, probucol and fenofibrate are also presented in the context of lipid-lowering and pleiotropic properties.
authors.affiliation: a Faculty of Health Sciences , School of Public Health Curtin University , Perth , WA , Australia and.|b Curtin Health Innovation Research Institute of Aging and Chronic Disease, Curtin University , Perth , WA , Australia.
authors.forename: Menuka
authors.initials: M
authors.lastname: Pallebage-Gamarallage
authors.affiliation: a Faculty of Health Sciences , School of Public Health Curtin University , Perth , WA , Australia and.|b Curtin Health Innovation Research Institute of Aging and Chronic Disease, Curtin University , Perth , WA , Australia.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takechi
authors.affiliation: a Faculty of Health Sciences , School of Public Health Curtin University , Perth , WA , Australia and.|b Curtin Health Innovation Research Institute of Aging and Chronic Disease, Curtin University , Perth , WA , Australia.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lam
authors.affiliation: a Faculty of Health Sciences , School of Public Health Curtin University , Perth , WA , Australia and.|b Curtin Health Innovation Research Institute of Aging and Chronic Disease, Curtin University , Perth , WA , Australia.
authors.forename: Mina
authors.initials: M
authors.lastname: Elahy
authors.affiliation: a Faculty of Health Sciences , School of Public Health Curtin University , Perth , WA , Australia and.|b Curtin Health Innovation Research Institute of Aging and Chronic Disease, Curtin University , Perth , WA , Australia.
authors.forename: John
authors.initials: J
authors.lastname: Mamo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001921:Brain / Q000098:blood supply* / Q000503:physiopathology*; D002196:Capillaries / Q000503:physiopathology*; D004041:Dietary Fats / Q000009:adverse effects*; D006801:Humans; D040242:Risk Reduction Behavior
chemical_list: D000893:Anti-Inflammatory Agents; D004041:Dietary Fats
keywords: Atherogenic fats; beta-amyloid; blood–brain barrier; capillary vasodilation; lipid-lowering agents; neurovascular inflammation; redox homeostasis