Mechanism of Ca2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP3 Receptor Channel Gating

Cheung, King‐Ho; Shineman, Diana W.; Müller, Marioly; Cárdenas, César; Mei, Lijuan; Yang, Jun; Tomita, Taisuke; Iwatsubo, Takeshi; Lee, Virginia M.‐Y.; Foskett, J. Kevin

doi:10.1016/j.neuron.2008.04.015

Cited by 416 publications

(484 citation statements)

References 69 publications

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“…The perturbation of calcium homeostasis may also contribute to a self-amplifying cascade of free radical-and Ca 2ϩ -mediated degenerative processes (48,50,51). Other sources of calcium dys-homeostasis in AD may include mutations in presenilins, which regulate calcium metabolism in the endoplasmic reticulum (51)(52)(53)(54)(55). Older literature has shown that AD-like neurofibrillary tangles of hyperphosphorylated tau protein may be caused by increased neuronal calcium (53).…”

Section: Discussionmentioning

confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

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Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A␤). We have hypothesized that the intrinsic A␤ calcium channel activity of the oligomeric A␤ polymer may be responsible for the neurotoxic properties of A␤, and that A␤ channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A␤ channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A␤ channel and protect neurons from A␤ toxicity. Both block the A␤ channel with similar potency (Ϸ500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery.brain ͉ neurodegeneration ͉ rational drug design ͉ drug ͉ toxicity A lzheimer's disease (AD) is a chronic neurodegenerative disease characterized behaviorally by progressive memory loss, and neuronal degeneration in the cerebral cortex, hippocampus, and elsewhere (1, 2). The neuropathology of AD is characterized by amyloid plaques and neuro-fibrillary tangles. The amyloid plaque material has been found to be composed principally of a 40Ϫ42-residue peptide, called amyloid ␤-peptide, or ''A␤'' (3). Both forms of A␤40/42 have been found to be kill neurons and certain other cells in culture. Altogether, these findings have provided strong support for the hypothesis that AD is due to neurotoxic effects of A␤ on susceptible neurons (4-10).The mechanism of A␤ neurotoxicity has been pursued for decades in hopes of translating such knowledge into a pharmaceutical therapy for AD. Cholinesterase inhibitors were the first generation of such candidate therapeutics (11-15). A second generation of candidate therapeutics has included a series of attempts to inhibit the formation of amyloid plaques. Active (16-23) and passive (24) immunization approaches are presently being tested. However, some patients in the active human immunization trials have developed meningoencephalitis (25,26). Yet another alternative has been to reduce the levels of A␤ in the brain by inhibiting the proteolytic enzymes associated with trimming APP into A␤ 40 or 42 (27-31).An entirely different approach to the mechanism of A␤ neurotoxicity has been developed following the observation that oligomers of A␤ peptides themselves formed calcium conducting channels in bilayer membranes in vitro (32)(33)(34)(35), and in intact neurons (36). The target of the A␤ peptide in biological and model membranes is phosphatidylserine (PS), the proapoptic signaling phospholipid (37). Subsequently the calcium channel properties of A␤ have been verified in many other laboratories (38-42). We and others have therefore hypothesized that calcium conducted into the target neurons by the A␤ channel might be respo...

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Section: Discussionmentioning

confidence: 99%

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Díaz

Šimáková

Jacobson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Aside from its Ca 2+ -dependent γ-cleavage-associated function, the presenilin/KChIP complex plays a role in controlling intracellular calcium signaling itself, since presenilins may directly interact with and facilitate the function of both IP3 and ryanodine receptors in the ER (Figure 1B) [48–51]. Leissring and coworkers found that the abnormally increased amplitude and accelerated decay of IP3-mediated Ca 2+ transients, observed in the presence of mutant PS1, returned to normal when KChIP3 (calsenilin) was co-expressed.…”

Section: Kchips Interact With Presenilinsmentioning

confidence: 99%

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Bähring

2018

Channels

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Kv channel-interacting proteins (KChIPs) belong to the neuronal calcium sensor (NCS) family of Ca2+-binding EF-hand proteins. KChIPs constitute a group of specific auxiliary β-subunits for Kv4 channels, the molecular substrate of transient potassium currents in both neuronal and non-neuronal tissues. Moreover, KChIPs can interact with presenilins to control ER calcium signaling and apoptosis, and with DNA to control gene transcription. Ca2+ binding via their EF-hands, with the consequence of conformational changes, is well documented for KChIPs. Moreover, the Ca2+ dependence of the presenilin/KChIP complex may be related to Alzheimer’s disease and the Ca2+ dependence of the DNA/KChIP complex to pain sensing. However, only in few cases could the Ca2+ binding to KChIPs be directly linked to the control of excitability in nerve and muscle cells known to express Kv4/KChIP channel complexes. This review summarizes current knowledge about the Ca2+ binding properties of KChIPs and the Ca2+ dependencies of macromolecular complexes containing KChIPs, including those with presenilins, DNA and especially Kv4 channels. The respective physiological or pathophysiolgical roles of Ca2+ binding to KChIPs are discussed.

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“…59 The mutated PS1 can also interact with the Ins(1,4,5)P 3 R to enhance its sensitivity. 60,61 Another important remodeling event associated with AD is a downregulation of the Ca 2+ buffer calbindin D-28k (CB). 62 It has been known for some time that during normal aging there are gradual changes in certain Ca 2+ signaling components that increase neuronal vulnerability to cell death stimuli.…”

Section: Bipolar Disordermentioning

confidence: 99%

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Berridge

2013

Prion

176

127

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Mechanism of Ca2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP3 Receptor Channel Gating

Cited by 416 publications

References 69 publications

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity

Kv channel-interacting proteins as neuronal and non-neuronal calcium sensors

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

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