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MAMs vary in thickness and length, impacting their functions. Here, we examined the effect of MAM thickness on A\u03b2 in our 3D neural model of AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We employed fluorescence resonance energy transfer (FRET) or fluorescence\u2010based MAM stabilizers, electron microscopy, A\u03b2 enzyme\u2010linked immunosorbent assay (ELISA), and live\u2010cell imaging with kymography to assess how stabilizing MAMs of different gap widths influence A\u03b2 production and MAM axonal mobility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Stabilizing tight MAMs (\u223c6\u00a0nm gap width) significantly increased A\u03b2 levels, whereas basal (\u223c25\u00a0nm) and loose MAMs (\u223c40\u00a0nm) maintained or reduced A\u03b2 levels, respectively. Tight MAMs reduced mitochondrial axonal velocity compared to basal MAMs, while loose MAMs showed severely reduced axonal distribution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Our findings suggest that stabilizing MAMs of specific gap widths, particularly in axons, without complete destabilization could be an effective therapeutic strategy for AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The stabilization of MAMs exacerbates or ameliorates A\u03b2 generation from AD neurons in a MAM gap width\u2010dependent manner.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A specific stabilization threshold within the MAM gap width spectrum shifts the amyloidogenic process to non\u2010amyloidogenic.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Tight MAMs slow down mitochondrial axonal transport compared to lose MAMs offering a quantitative method for measuring MAM stabilization.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.14417","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T05:58:52Z","timestamp":1734933532000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Stabilization of mitochondria\u2010associated endoplasmic reticulum membranes regulates A\u03b2 generation in a three\u2010dimensional neural model of Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Jacob C.","family":"Zellmer","sequence":"first","affiliation":[{"name":"Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Henry and Allison McCance Center for\u00a0Brain Health Department of Neurology Massachusetts General Hospital, Harvard Medical School  Charlestown Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina B.","family":"Tarantino","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Henry and Allison McCance Center for\u00a0Brain Health Department of Neurology Massachusetts General Hospital, Harvard Medical School  Charlestown Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Kim","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Henry and Allison McCance Center for\u00a0Brain Health Department of Neurology Massachusetts General Hospital, Harvard Medical School  Charlestown Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selene","family":"Lomoio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Maesako","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Research Unit MassGeneral Institute for Neurodegenerative Disease Massachusetts General Hospital\/Harvard Medical School  Charlestown Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Hajn\u00f3czky","sequence":"additional","affiliation":[{"name":"MitoCare Center Department of Pathology Anatomy &amp; Cell Biology Thomas Jefferson University  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raja","family":"Bhattacharyya","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit MassGeneral Institute for Neurodegenerative Disease Henry and Allison McCance Center for\u00a0Brain Health Department of Neurology Massachusetts General Hospital, Harvard Medical School  Charlestown Massachusetts 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