title: Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca(2+) homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca(2+) signaling, predominantly through the ER-localized inositol triphosphate (IP(3)) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca(2+) upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca(2+) imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca(2+) signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca(2+) aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.
authors.affiliation: Department of Neuroscience, Rosalind Franklin University/The Chicago Medical School, North Chicago, IL, USA.
authors.forename: Shreaya
authors.initials: S
authors.lastname: Chakroborty
authors.forename: Clark
authors.initials: C
authors.lastname: Briggs
authors.forename: Megan B
authors.initials: MB
authors.lastname: Miller
authors.forename: Ivan
authors.initials: I
authors.lastname: Goussakov
authors.forename: Corinne
authors.initials: C
authors.lastname: Schneider
authors.forename: Joyce
authors.initials: J
authors.lastname: Kim
authors.forename: Jaime
authors.initials: J
authors.lastname: Wicks
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Vincent
authors.initials: V
authors.lastname: Conklin
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Cameransi
authors.forename: Grace E
authors.initials: GE
authors.lastname: Stutzmann
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D003620:Dantrolene / Q000494:pharmacology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D019837:Ryanodine Receptor Calcium Release Channel; D003620:Dantrolene; D002118:Calcium