Loss of Caveolin-1 Accelerates Neurodegeneration and Aging

Abstract

BackgroundThe 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.Methodology/Principal FindingsWe 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.ConclusionsTherefore, 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.

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

“…These results extend those that have shown that the loss of Cav-1, either through siRNA or transgenic models, can blunt neuroprotection (9) and metabotropic glutamate receptor-mediated long-term depression (43,59) and accelerate a neurodegenerative phenotype (32,60,61). Our findings obtained with siRNA-mediated Cav-1 knockdown extend the role of Cav-1 in neuronal signaling to a variety of receptors in addition to glutamate.…”

“…Such features include altered glutamate receptor signaling (9,43,59), motor and behavioral abnormalities, increased ischemic cerebral injury, and impaired spatial memory and cholinergic function (60 -62). Other recent evidence has demonstrated that the localization of synaptic signaling components in neuronal membrane/lipid rafts and synaptosomes is reduced in brains from aged WT and young Cav-1 KO mice and that Cav-1 KO mice develop a neuropathological phenotype similar to that of Alzheimer's disease (32).…”

“…Moreover, Cav-1 KO mice exhibit reduced synaptic signaling and scaffolding proteins in hippocampal synaptosomes, and this is associated with an inability to be preconditioned against lethal ischemia (32). We therefore tested whether neuron-targeted Cav-1 expression would enhance membrane/lipid raft formation and expression of synaptic receptors and, in addition, would promote prosurvival signaling.…”

“…We therefore tested whether neuron-targeted Cav-1 expression would enhance membrane/lipid raft formation and expression of synaptic receptors and, in addition, would promote prosurvival signaling. SynCav1, a vector that contains the synapsin promoter upstream of Cav, specifically targets Cav-1 expression to neurons (32) (Fig. 1).…”

Molecular and structural bases for postsynaptic signal processing: interaction between postsynaptic density and postsynaptic membrane rafts

“…Furthermore, augmentation of synaptic raft function may lead to strengthening and repair of synaptic function. 96,125 The knowledge gained will be important for developing therapeutical approaches to neurological and psychiatric diseases caused by synapse dysfunctions.…”