title: Loss of caveolin-1 accelerates neurodegeneration and aging.
abstract: BACKGROUND
  The aged brain exhibits a loss in gray matter and a decrease in spines and synaptic densities that may represent a sequela for neurodegenerative diseases such as Alzheimer's. Membrane/lipid rafts (MLR), discrete regions of the plasmalemma enriched in cholesterol, glycosphingolipids, and sphingomyelin, are essential for the development and stabilization of synapses. Caveolin-1 (Cav-1), a cholesterol binding protein organizes synaptic signaling components within MLR. It is unknown whether loss of synapses is dependent on an age-related loss of Cav-1 expression and whether this has implications for neurodegenerative diseases such as Alzheimer's disease.
  
  
  RESULTS
  We analyzed brains from young (Yg, 3-6 months), middle age (Md, 12 months), aged (Ag, >18 months), and young Cav-1 KO mice and show that localization of PSD-95, NR2A, NR2B, TrkBR, AMPAR, and Cav-1 to MLR is decreased in aged hippocampi. Young Cav-1 KO mice showed signs of premature neuronal aging and degeneration. Hippocampi synaptosomes from Cav-1 KO mice showed reduced PSD-95, NR2A, NR2B, and Cav-1, an inability to be protected against cerebral ischemia-reperfusion injury compared to young WT mice, increased Aβ, P-Tau, and astrogliosis, decreased cerebrovascular volume compared to young WT mice. As with aged hippocampi, Cav-1 KO brains showed significantly reduced synapses. Neuron-targeted re-expression of Cav-1 in Cav-1 KO neurons in vitro decreased Aβ expression.
  
  
  CONCLUSIONS
  Therefore, Cav-1 represents a novel control point for healthy neuronal aging and loss of Cav-1 represents a non-mutational model for Alzheimer's disease.
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Head
authors.forename: Jason N
authors.initials: JN
authors.lastname: Peart
authors.forename: Mathivadhani
authors.initials: M
authors.lastname: Panneerselvam
authors.forename: Takaakira
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Pearn
authors.forename: Ingrid R
authors.initials: IR
authors.lastname: Niesman
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bonds
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schilling
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: John
authors.initials: J
authors.lastname: Headrick
authors.forename: Sameh S
authors.initials: SS
authors.lastname: Ali
authors.forename: David M
authors.initials: DM
authors.lastname: Roth
authors.forename: Piyush M
authors.initials: PM
authors.lastname: Patel
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D021962:Membrane Microdomains; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
chemical_list: D051242:Caveolin 1