Cognitive decline is emerging as one of the greatest health problems in the elderly population, with approximately half of all adults over the age of 85 suffering from Alzheimer's disease (AD). The number of individuals afflicted with cognitive decline will increase as the population ages. Age alone increases the risk of stroke and the prevalence of AD and other forms of dementia. Learning, memory and the development of neurons are dependent upon synapses. Receptors and associated proteins aggregate to mold and shape postsynaptic densities in order to permit high fidelity signal transduction leading to rapid regulation of neuronal function, an organization which is altered with age. A number of theories have been proposed to account for this aging deficit. These theories suggest a genetic, a biochemical, or a physiologic component. Though the mechanisms that underlie age-related neurodegeneration and cognitive decline are not clear, they likely involve abnormalities in the organization of pro-survival and pro-growth neuronal signaling proteins and molecules that are a combined result of genetic, biochemical, and physiologic deficiencies. Key to efficient neuronal signaling are membrane/lipid rafts (MLR), plasmalemmal microdomains enriched in sphingolipids, cholesterol, and scaffolding proteins;they serve to organize membrane signaling and trafficking. MLR facilitate coordinated, precise and rapid regulation of cell function. MLR are also concentrated within growth cones and are essential for axonal growth and guidance and are essential for the development and stabilization of synapses. A key component of MLR is caveolin-1 (Cav-1), a cholesterol binding protein that organizes and scaffolds not only a multitude of receptors including NMDAR, AMPAR, GPCRs, and TrkR, but also signaling molecules such as Src and ERK1/2 and those that regulate cAMP formation. Hence, MLR contain the receptors and signaling molecules that are critical to neuronal survival and growth. Preliminary data from our laboratory demonstrate that middle aged (12 m) and aged mice (>18 m) exhibit significant decreases in MLR, reduced synaptosomes and their associated proteins (Cav-1, NMDAR, AMPAR, TrkR, and PSD-95) and synapses in the hippocampus;young Cav-1 KO mice exhibit early aging neuropathology. Importantly, Cav-1 overexpression in neurons: 1) increases MLR, NMDAR, AMPAR, and TrkB;2) enhances BDNF-mediated phosphorylation of TrkB, Akt, and ERK1/2;3) enhances NMDAR- mediated activation of P-Src, P-CaMKII, and P-ERK1/2;4) increases NMDAR, Dopamine 1 receptor (D1R), 5-HT6, and forskolin-mediated cAMP formation;and 5) increases dendritic sprouting and branching. Thus, Cav-1 serves as a nexus for pro-survival and pro-growth neuronal signaling. In essence, the single intervention of Cav-1 overexpression in neurons leads to the upregulation of a multitude of signaling pathways that significantly enhance endogenous brain repair and regeneration. As such, it may provide a control point that can be therapeutically targeted to restore neuronal function in the aging Veteran population.
Age-related neurodegenerative diseases are the most common causes of morbidity in the Veteran population. As this population ages, morbidity attendant and neurodegenerative disease will increase in prevalence. Approaches to enhance endogenous protective signaling may reduce the vulnerability of the brain to neurodegeneration. There also exists the potential for enhancing cognitive function during the latter stages of life. The proposed research will attempt to develop a novel approach to enhance neuronal survival by restoring normal caveolin levels in neurons, restoring normal levels of glutamate receptors in synapses and restoration/enhancement of endogenous neuroprotective, pro-survival and pro-growth signaling. As such, the research has direct clinical relevance to the long-term health of our Veterans.
|Schilling, J M; Kassan, A; Mandyam, C et al. (2017) Inhibition of p75 neurotrophin receptor does not rescue cognitive impairment in adulthood after isoflurane exposure in neonatal mice. Br J Anaesth 119:465-471|
|Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411|
|Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110|
|Somkuwar, Sucharita S; Fannon, McKenzie J; Head, Brian P et al. (2016) Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function. Neuroscience 328:147-56|
|Head, Brian P; Patel, Hemal H; Insel, Paul A (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 1838:532-45|
|Schilling, Jan M; Cui, Weihua; Godoy, Joseph C et al. (2014) Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry. Behav Brain Res 267:6-11|
|Wang, Jiawan; Schilling, Jan M; Niesman, Ingrid R et al. (2014) Cardioprotective trafficking of caveolin to mitochondria is Gi-protein dependent. Anesthesiology 121:538-48|
|Niesman, Ingrid R; Zemke, Nathan; Fridolfsson, Heidi N et al. (2013) Caveolin isoform switching as a molecular, structural, and metabolic regulator of microglia. Mol Cell Neurosci 56:283-97|
|Stary, Creed M; Tsutsumi, Yasuo M; Patel, Piyush M et al. (2012) Caveolins: targeting pro-survival signaling in the heart and brain. Front Physiol 3:393|