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Article ; Online: Alzheimer's disease - Where do we go from here?

Bezprozvanny, Ilya

Biochemical and biophysical research communications

2022 Volume 633, Page(s) 72–76

MeSH term(s)	Humans ; Alzheimer Disease
Language	English
Publishing date	2022-09-12
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2022.08.075
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Article ; Online: Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease.

Kim, Meewhi / Bezprozvanny, Ilya

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) ... ...

Abstract	Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the "amyloid hypothesis" that states that the resulting increase in Aβ42:Aβ40 ratio leads to "toxic gain of function" due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that "loss of function" of γ-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40/Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the "loss of γ-secretase function" hypothesis than with the "toxic gain of Aβ42 function" idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Mutation ; Mice, Knockout ; Presenilin-1/genetics ; Presenilin-1/metabolism
Chemical Substances	Amyloid beta-Protein Precursor ; Amyloid beta-Peptides ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Presenilin-1
Language	English
Publishing date	2023-01-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24032092
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Article: "Dirty Dancing" of Calcium and Autophagy in Alzheimer's Disease.

Zhang, Hua / Bezprozvanny, Ilya

Life (Basel, Switzerland)

2023 Volume 13, Issue 5

Abstract: Alzheimer's disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium ( ... ...

Abstract	Alzheimer's disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium (Ca
Language	English
Publishing date	2023-05-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life13051187
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Article ; Online: Structure-Based Modeling of Sigma 1 Receptor Interactions with Ligands and Cholesterol and Implications for Its Biological Function.

Kim, Meewhi / Bezprozvanny, Ilya

International journal of molecular sciences

2023 Volume 24, Issue 16

Abstract: The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. ... ...

Abstract	The sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R plays an important role in neuronal health and it is an established therapeutic target for neurodegenerative and neuropsychiatric disorders. Despite its importance in physiology and disease, the biological function of S1R is poorly understood. To gain insight into the biological and signaling functions of S1R, we took advantage of recently reported crystal structures of human and
MeSH term(s)	Humans ; Cholesterol ; Computational Biology ; Endoplasmic Reticulum ; Ligands ; Models, Structural ; Receptors, sigma/metabolism ; Sigma-1 Receptor
Chemical Substances	Cholesterol (97C5T2UQ7J) ; Ligands ; Receptors, sigma
Language	English
Publishing date	2023-08-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241612980
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Article ; Online: Potential direct role of synuclein in dopamine transport and its implications for Parkinson's disease pathogenesis.

Kim, Meewhi / Bezprozvanny, Ilya

Biochemical and biophysical research communications

2023 Volume 671, Page(s) 18–25

Abstract: Parkinson Disease (PD) is a progressive neurodegenerative disorder that is caused by dysfunction and death of dopaminergic neurons. Mutations in the gene encoding α-synuclein (ASYN) have been linked with familial PD (FPD). Despite important role of ASYN ... ...

Abstract	Parkinson Disease (PD) is a progressive neurodegenerative disorder that is caused by dysfunction and death of dopaminergic neurons. Mutations in the gene encoding α-synuclein (ASYN) have been linked with familial PD (FPD). Despite important role of ASYN in PD pathology, its normal biological function has not been clarified, although direct action of ASYN in synaptic transmission and dopamine (DA
MeSH term(s)	Humans ; Parkinson Disease/metabolism ; Dopamine/metabolism ; alpha-Synuclein/genetics ; alpha-Synuclein/metabolism ; Mutation ; Dopaminergic Neurons/pathology ; Synaptic Transmission
Chemical Substances	Dopamine (VTD58H1Z2X) ; alpha-Synuclein
Language	English
Publishing date	2023-06-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2023.05.110
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Calcium hypothesis of neurodegeneration - An update.

Bezprozvanny, Ilya

Biochemical and biophysical research communications

2019 Volume 520, Issue 4, Page(s) 667–669

MeSH term(s)	Animals ; Calcium/metabolism ; Humans ; Nerve Degeneration/metabolism
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2019.10.016
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ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Author Correction: SpineTool is an open-source software for analysis of morphology of dendritic spines.

Pchitskaya, Ekaterina / Vasiliev, Peter / Smirnova, Daria / Chukanov, Vyacheslav / Bezprozvanny, Ilya

Scientific reports

2024 Volume 14, Issue 1, Page(s) 4107

Language	English
Publishing date	2024-02-19
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-54127-4
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Article ; Online: Expansion Microscopy Application for Calcium Protein Clustering Imaging in Cells and Brain Tissues.

Rakovskaya, Anastasiya / Chigriai, Margarita / Bezprozvanny, Ilya / Pchitskaya, Ekaterina

Current protocols

2023 Volume 3, Issue 6, Page(s) e789

Abstract: Many biological studies require high-resolution imaging and subsequent analysis of cell organelles and molecules. Some membrane proteins form tight clusters, and this process is directly linked to their function. In most studies, these small protein ... ...

Abstract	Many biological studies require high-resolution imaging and subsequent analysis of cell organelles and molecules. Some membrane proteins form tight clusters, and this process is directly linked to their function. In most studies, these small protein clusters have been investigated by total internal reflection fluorescence (TIRF) microscopy, which enables imaging with high spatial resolution within 100 nm of the membrane surface. Recently developed expansion microscopy (ExM) makes it possible to achieve nanometer resolution using a conventional fluorescence microscope by physically expanding the sample. In this article, we describe implementation of ExM for imaging of protein clusters formed by the endoplasmic reticulum (ER) calcium sensor protein STIM1. This protein translocates during ER store depletion and forms clusters that support contact with plasma membrane (PM) calcium-channel proteins. ER calcium channels such as the type 1 inositol triphosphate receptor (IP3R) also form clusters, but their investigation by TIRF microscopy is impossible due to the large distance from the PM. In this article, we demonstrate how to investigate IP3R clustering using ExM in hippocampal brain tissues. We compare IP3R clustering in the CA1 area of the hippocampus of wild-type and 5xFAD Alzheimer's disease model mice. To facilitate future applications, we describe experimental protocols and image processing guidelines for application of ExM to membrane and ER protein clustering studies in cultured cells and brain tissues. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Expansion microscopy application for protein cluster visualization in cells Alternate Protocol: Expansion microscopy application for protein cluster visualization in brain tissues Basic Protocol 2: Protein cluster analysis of expansion microscopy images using ImageJ and Icy software.
MeSH term(s)	Animals ; Mice ; Calcium/metabolism ; Inositol 1,4,5-Trisphosphate Receptors/metabolism ; Microscopy, Fluorescence/methods ; Cluster Analysis ; Brain/diagnostic imaging
Chemical Substances	Calcium (SY7Q814VUP) ; Inositol 1,4,5-Trisphosphate Receptors
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.789
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Article ; Online: Activation of Gq-Coupled Receptors in Astrocytes Restores Cognitive Function in Alzheimer's Disease Mice Model.

Gerasimov, Evgenii / Bezprozvanny, Ilya / Vlasova, Olga L

International journal of molecular sciences

2023 Volume 24, Issue 12

Abstract: Alzheimer's disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aβ amyloid clearance from the brain. However, some ... ...

Abstract	Alzheimer's disease (AD) is one of the most widespread neurodegenerative diseases. Most of the current AD therapeutic developments are directed towards improving neuronal cell function or facilitating Aβ amyloid clearance from the brain. However, some recent evidence suggests that astrocytes may play a significant role in the pathogenesis of AD. In this paper, we evaluated the effects of the optogenetic activation of Gq-coupled exogenous receptors expressed in astrocytes as a possible way of restoring brain function in the AD mouse model. We evaluated the effects of the optogenetic activation of astrocytes on long-term potentiation, spinal morphology and behavioral readouts in 5xFAD mouse model of AD. We determined that in vivo chronic activation of astrocytes resulted in the preservation of spine density, increased mushroom spine survival, and improved performance in cognitive behavioral tests. Furthermore, chronic optogenetic stimulation of astrocytes resulted in the elevation of EAAT-2 glutamate uptake transporter expression, which could be a possible explanation for the observed in vivo neuroprotective effects. The obtained results suggest that the persistent activation of astrocytes may be considered a potential therapeutic approach for the treatment of AD and possibly other neurodegenerative disorders.
MeSH term(s)	Mice ; Animals ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Astrocytes/metabolism ; Cognition ; Brain/metabolism ; Disease Models, Animal ; Mice, Transgenic
Chemical Substances	Amyloid beta-Peptides
Language	English
Publishing date	2023-06-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24129969
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Article ; Online: Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.

Kim, Meewhi / Bezprozvanny, Ilya

International journal of molecular sciences

2021 Volume 22, Issue 24

Abstract: Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) ...

Abstract	Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations-M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid Precursor Protein Secretases/chemistry ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/chemistry ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Humans ; Models, Molecular ; Mutation ; Presenilin-1/chemistry ; Presenilin-1/genetics ; Presenilin-1/metabolism ; Presenilin-2/chemistry ; Presenilin-2/genetics ; Presenilin-2/metabolism ; Protein Conformation ; Protein Domains ; Protein Stability
Chemical Substances	APP protein, human ; Amyloid beta-Protein Precursor ; PSEN1 protein, human ; PSEN2 protein, human ; Presenilin-1 ; Presenilin-2 ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2021-12-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222413600
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