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 Ca2+ 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 Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ 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 Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ 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 Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.

Aβ42 oligomers selectively disrupt neuronal calcium release

“…Of note, the impairment of synaptic transmission caused by exogenously applied Ab42o has the same time window observed for alterations in neuronal Ca 2þ stores and a similar insensitivity to NMDAR blockade (Lee et al, 2013). As a whole, our data are fully consistent with a central role of aberrant ER Ca 2þ signaling in neuronal aging and cognitive decline (Berridge, 2014;Stutzmann and Mattson, 2011) and the use of ER Ca 2þ channel stabilizers in clinical AD trials (Chakroborty and Stutzmann, 2014;Chakroborty et al, 2012;Oules et al, 2012).…”

“…Although increase in RyR3 transcript seems to have a neuroprotective effect (Supnet et al, 2010), it has been suggested that upregulation of RyR2, a finding common to several AD mouse models, could be an additional mechanism that contributes to synaptic failure and memory dysfunction in AD and in the aged brain (Bruno et al, 2012;Chakroborty et al, 2009;Kipanyula et al, 2012;Toescu and Verkhratsky, 2007). Consistently, dantrolene treatment is protective in APP mice and restores RyR2 levels (Chakroborty et al, 2012;Oules et al, 2012). At variance with rat hippocampal neurons (Paula-Lima et al, 2011), we did not observe significant increase in protein and transcript levels of RyR2 (and RyR3) following 1-hour treatment of mouse cortical neurons with Ab42o.…”

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

“…The protective effect of dantrolene treatment on WFS1-deficient cells suggests that dysregulated cellular calcium homeostasis plays a role in the disease progression of Wolfram syndrome. In addition, it has been shown that stabilizing ER calcium channel function could prevent the progression of neurodegeneration in a mouse model of Alzheimer's disease (48). Therefore, modulating calcium levels may be an effective way to treat Wolfram syndrome or other ER diseases.…”

Dantrolene, A Treatment for Alzheimer Disease?

“…In December of 2012, Chakroborty et al 106 reported sub-chronically short-term (4 weeks) treatment of AD models with dantrolene. Using patch clamp recordings and 2-photon Ca 2+ imaging of hippocampal slices, the authors found that ER Ca 2+ signaling is fully normalized in dendritic compartments in dantrolene treated early and later-stage AD mice.…”