Ilya Bezprozvanny on Mutant Presenilin Skews Calcium Homeostasis by Chomping on ER Sensor

COMMENT This is an interesting paper that suggests a potential mechanism for reduction of store-operated calcium entry (SOC) in AD neurons. Our laboratory previously suggested that reduction in SOC calcium entry is one of the potential reasons for synaptic ...

Ilya Bezprozvanny on Shielding Synaptic Glutamate Receptor from Aβ Preserves Memory in Mice

COMMENT This is an interesting paper by Hamilton and colleagues that supports the idea that overactivation of mGluR5 by amyloid oligomers, and resulting dysregulated calcium signaling at synaptic locations, play an important role in AD. Previous studies already ...

Ilya Bezprozvanny on Reversal of Aging-Related Neuronal Ca2+ Dysregulation and Cognitive Impairment by Delivery of a Transgene Encoding FK506-Binding Protein 12.6/1b to the Hippocampus.

COMMENT This is an interesting and elegant study that further supports the connection between excessive ryanodine receptor (RyanR)-mediated calcium release from neuronal endoplasmic reticulum (ER) and memory defects in aging and AD. The authors demonstrate here ...

Ilya Bezprozvanny on Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease.

COMMENT A number of presenilin- and APP-based models of familial Alzheimer's disease (FAD) have been previously generated, but most of these rely on transgenic overexpression. An APP-knock-in (KI) mouse was generated recently at RIKEN (Saito et al., 2014). ...

Ilya Bezprozvanny on ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43.

COMMENT The finding of a VAPB-PTPIP51 interaction supporting the ER-mitochondria association is interesting and convincing. The effects of TDP-43 overexpression suggest a potential role for TDP-43 in modulating this ER-mitochondrial association and intracellular ...

Ilya Bezprozvanny on Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate.

COMMENT This paper by Angelo Demuro and Ian Parker reports very careful examination of Ca2+ signaling effects by intracellular amyloid-β oligomers. They used a Xenopus oocyte model system. In previous studies these authors used a similar approach to evaluate Ca2+ ...

Ilya Bezprozvanny on First Crystal Structure of a Presenilin

COMMENT The paper by Li et al. is a real tour de force that offers the first atomic resolution information about the three-dimensional structure of presenilins. Multiple laboratories around the world attempted to crystallize presenilins previously but have not ...

Ilya Bezprozvanny on Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer's disease mice.

COMMENT In her previous series of papers, Dr. Stutzmann reported a number of abnormalities in calcium signaling and synaptic function resulting from presenilin FAD mutations. In the present paper, her group offers a comprehensive and physiologically relevant ...

Ilya Bezprozvanny on Single-channel Ca(2+) imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology.

COMMENT This is an elegant paper that uses the “optical patch clamp” method to resolve individual calcium transients resulting from incorporation of Aβ42 oligomers into the membrane. Previous electrophysiological recordings of Aβ42-induced channels in lipid ...

Ilya Bezprozvanny on A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis.

COMMENT This is a very interesting basic science paper for people who focus on synaptic vesicle turnover in the synapse. It will be interesting to see if mutations in human homologs of Flower are linked to any neurodegenerative of psychiatric disorders. ilya ...

Ilya Bezprozvanny on Presenilins, Ryanodine Receptors—Conspirators in Neurotransmission?

COMMENT A number of previous studies indicated that FAD mutations and genetic deletions of presenilins are linked with abnormal ER Ca2+ homeostasis (reviewed in 1,2). These two new papers provide a first look at changes in synaptic function resulting from such ER ...

Ilya Bezprozvanny on Perpetrator and Savior—Presenilins Cut Both Ways

COMMENT The paper by Tabuchi at al. is a fascinating study that uses genetic approach to investigate the importance of γ-secretase activity for neuronal survival. The authors generated floxed nicastrin mice and crossed them with the α-CaMKII-Cre transgenic driver ...

Ilya Bezprozvanny on NAADP mobilizes calcium from acidic organelles through two-pore channels.

COMMENT It is well established that most of intracellular Ca2+ is stored in the endoplasmic reticulum (ER) and that stored Ca2+ can be released by activation of InsP3-gated InsP3R channels or Ca2+-gated RyanR channels in the ER. The potential importance of ...

Ilya Bezprozvanny on A polymorphism in CALHM1 influences Ca2+ homeostasis, Abeta levels, and Alzheimer's disease risk.

COMMENT Amyloid-calcium Connection Is Getting More Intimate The recent paper by Ute Dreses-Werringloer and colleagues provides a very interesting and unexpected connection between Ca2+ signaling and amyloid. By focusing on LOAD locus 10q24.33, the authors ...

Ilya Bezprozvanny on Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating.

COMMENT A number of previous reports linked FAD-causing mutations in presenilins with abnormal endoplasmic reticulum (ER) Ca2+ signaling (1-3). Biochemical and functional interactions have been previously uncovered between presenilins and intracellular Ca2+ ...