Stabilization of Mitochondria-associated Endoplasmic Reticulum Membranes Regulates Aβ Generation in a Three-dimensional Neural Model of Alzheimer's Disease

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2024 Dec 23

PMID 39713841

Authors

Jacob C Zellmer

Marina B Tarantino

Michelle Kim

Selene Lomoio

Masato Maesako

Gyorgy Hajnoczky

Raja Bhattacharyya

Affiliations

Soon will be listed here.

Abstract

Introduction: We previously demonstrated that regulating mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) affects axonal Aβ generation in a well-characterized three-dimensional (3D) neural Alzheimer's disease (AD) model. MAMs vary in thickness and length, impacting their functions. Here, we examined the effect of MAM thickness on Aβ in our 3D neural model of AD.

Methods: We employed fluorescence resonance energy transfer (FRET) or fluorescence-based MAM stabilizers, electron microscopy, Aβ enzyme-linked immunosorbent assay (ELISA), and live-cell imaging with kymography to assess how stabilizing MAMs of different gap widths influence Aβ production and MAM axonal mobility.

Results: Stabilizing tight MAMs (∼6 nm gap width) significantly increased Aβ levels, whereas basal (∼25 nm) and loose MAMs (∼40 nm) maintained or reduced Aβ levels, respectively. Tight MAMs reduced mitochondrial axonal velocity compared to basal MAMs, while loose MAMs showed severely reduced axonal distribution.

Discussion: Our findings suggest that stabilizing MAMs of specific gap widths, particularly in axons, without complete destabilization could be an effective therapeutic strategy for AD.

Highlights: The stabilization of MAMs exacerbates or ameliorates Aβ generation from AD neurons in a MAM gap width-dependent manner. A specific stabilization threshold within the MAM gap width spectrum shifts the amyloidogenic process to non-amyloidogenic. Tight MAMs slow down mitochondrial axonal transport compared to lose MAMs offering a quantitative method for measuring MAM stabilization.

Citing Articles

Stabilization of mitochondria-associated endoplasmic reticulum membranes regulates Aβ generation in a three-dimensional neural model of Alzheimer's disease.

Zellmer J, Tarantino M, Kim M, Lomoio S, Maesako M, Hajnoczky G Alzheimers Dement. 2024; 21(2):e14417.

PMID: 39713841 PMC: 11848173. DOI: 10.1002/alz.14417.

References

Rountree S, Atri A, Lopez O, Doody R . Effectiveness of antidementia drugs in delaying Alzheimer's disease progression. Alzheimers Dement. 2012; 9(3):338-45. DOI: 10.1016/j.jalz.2012.01.002. View

Szymanski J, Janikiewicz J, Michalska B, Patalas-Krawczyk P, Perrone M, Ziolkowski W . Interaction of Mitochondria with the Endoplasmic Reticulum and Plasma Membrane in Calcium Homeostasis, Lipid Trafficking and Mitochondrial Structure. Int J Mol Sci. 2017; 18(7). PMC: 5536064. DOI: 10.3390/ijms18071576. View

Song J, Yuan C, Li W, Gao T, Lu X, Wang L . APP palmitoylation is involved in the increase in Aβ induced by aluminum. Brain Res. 2021; 1774:147709. DOI: 10.1016/j.brainres.2021.147709. View

Bravo R, Vicencio J, Parra V, Troncoso R, Munoz J, Bui M . Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci. 2011; 124(Pt 13):2143-52. PMC: 3113668. DOI: 10.1242/jcs.080762. View

Schon E, Area-Gomez E . Mitochondria-associated ER membranes in Alzheimer disease. Mol Cell Neurosci. 2012; 55:26-36. DOI: 10.1016/j.mcn.2012.07.011. View

Volgyi K, Badics K, Sialana F, Gulyassy P, Udvari E, Kis V . Early Presymptomatic Changes in the Proteome of Mitochondria-Associated Membrane in the APP/PS1 Mouse Model of Alzheimer's Disease. Mol Neurobiol. 2018; 55(10):7839-7857. DOI: 10.1007/s12035-018-0955-6. View

Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P . On the role of Mitofusin 2 in endoplasmic reticulum-mitochondria tethering. Proc Natl Acad Sci U S A. 2017; 114(12):E2266-E2267. PMC: 5373360. DOI: 10.1073/pnas.1616040114. View

Zellmer J, Lomoio S, Tanzi R, Bhattacharyya R . Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD). J Vis Exp. 2025; 215. DOI: 10.3791/66129. View

Bhattacharyya R, Fenn R, Barren C, Tanzi R, Kovacs D . Palmitoylated APP Forms Dimers, Cleaved by BACE1. PLoS One. 2016; 11(11):e0166400. PMC: 5119739. DOI: 10.1371/journal.pone.0166400. View

10.

Fang C, Bourdette D, Banker G . Oxidative stress inhibits axonal transport: implications for neurodegenerative diseases. Mol Neurodegener. 2012; 7:29. PMC: 3407799. DOI: 10.1186/1750-1326-7-29. View

11.

Erpapazoglou Z, Mouton-Liger F, Corti O . From dysfunctional endoplasmic reticulum-mitochondria coupling to neurodegeneration. Neurochem Int. 2017; 109:171-183. DOI: 10.1016/j.neuint.2017.03.021. View

12.

Weber F, Wunsch B . Medicinal Chemistry of σ Receptor Ligands: Pharmacophore Models, Synthesis, Structure Affinity Relationships, and Pharmacological Applications. Handb Exp Pharmacol. 2017; 244:51-79. DOI: 10.1007/164_2017_33. View

13.

Anastasia I, Ilacqua N, Raimondi A, Lemieux P, Ghandehari-Alavijeh R, Faure G . Mitochondria-rough-ER contacts in the liver regulate systemic lipid homeostasis. Cell Rep. 2021; 34(11):108873. DOI: 10.1016/j.celrep.2021.108873. View

14.

Hadwen J, Schock S, Mears A, Yang R, Charron P, Zhang L . Transcriptomic RNAseq drug screen in cerebrocortical cultures: toward novel neurogenetic disease therapies. Hum Mol Genet. 2018; 27(18):3206-3217. DOI: 10.1093/hmg/ddy221. View

15.

Lin C, Herisson F, Le H, Jaafar N, Chetal K, Oram M . Mast cell deficiency improves cognition and enhances disease-associated microglia in 5XFAD mice. Cell Rep. 2023; 42(9):113141. PMC: 10634538. DOI: 10.1016/j.celrep.2023.113141. View

16.

Salaciak K, Pytka K . Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders. Neurosci Biobehav Rev. 2021; 132:1114-1136. PMC: 8559442. DOI: 10.1016/j.neubiorev.2021.10.037. View

17.

Maesako M, Horlacher J, Zoltowska K, Kastanenka K, Kara E, Svirsky S . Pathogenic PS1 phosphorylation at Ser367. Elife. 2017; 6. PMC: 5279945. DOI: 10.7554/eLife.19720. View

18.

Stokin G, Lillo C, Falzone T, Brusch R, Rockenstein E, Mount S . Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005; 307(5713):1282-8. DOI: 10.1126/science.1105681. View

19.

Fallica A, Pittala V, Modica M, Salerno L, Romeo G, Marrazzo A . Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective. J Med Chem. 2021; 64(12):7926-7962. PMC: 8279423. DOI: 10.1021/acs.jmedchem.0c02265. View

20.

Katona M, Bartok A, Nichtova Z, Csordas G, Berezhnaya E, Weaver D . Capture at the ER-mitochondrial contacts licenses IP receptors to stimulate local Ca transfer and oxidative metabolism. Nat Commun. 2022; 13(1):6779. PMC: 9646835. DOI: 10.1038/s41467-022-34365-8. View