{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T18:19:44Z","timestamp":1790965184784,"version":"4.1.0"},"reference-count":90,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T00:00:00Z","timestamp":1567987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["2R25GM077634-10"],"award-info":[{"award-number":["2R25GM077634-10"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Army Research Office and Department of Defense Research and Education Program for Historically Black Colleges and Universities and Minority-Serving Institutions","award":["W911NF-15-1-0053"],"award-info":[{"award-number":["W911NF-15-1-0053"]}]},{"name":"Coins for Alzheimer\u2019s Research Trust","award":["Bahr - Lys Mod"],"award-info":[{"award-number":["Bahr - Lys Mod"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer\u2019s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein\/presenilin-1 (APP\/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson\u2019s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP\/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid \u03b2 42 (A\u03b242) degradation product A\u03b238, and this indicator of A\u03b242 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted A\u03b242 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing A\u03b2 deposits as well. PADK also reduced amyloidogenic peptides and \u03b1-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP\/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.<\/jats:p>","DOI":"10.3390\/ijms20184432","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T11:26:17Z","timestamp":1568028377000},"page":"4432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["The Role of Lysosomes in a Broad Disease-Modifying Approach Evaluated across Transgenic Mouse Models of Alzheimer\u2019s Disease and Parkinson\u2019s Disease and Models of Mild Cognitive Impairment"],"prefix":"10.3390","volume":"20","author":[{"given":"Jeannie","family":"Hwang","sequence":"first","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice M.","family":"Estick","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA"},{"name":"Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5938-0699","authenticated-orcid":false,"given":"Uzoma S.","family":"Ikonne","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Butler","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences and the Neurosciences Program, University of Connecticut, Storrs, CT 06269, USA"},{"name":"Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan C.","family":"Pait","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Chemistry and Physics, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyndsie H.","family":"Elliott","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ruiz","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlan","family":"Smith","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Molecular Biotechnology Program University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.","family":"Rentschler","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cary","family":"Mundell","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael F.","family":"Almeida","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole Stumbling","family":"Bear","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Locklear","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Abumohsen","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecily M.","family":"Ivey","sequence":"additional","affiliation":[{"name":"William C. Friday Laboratory, Biotechnology Research and Training Center, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"},{"name":"Department of Biology, University of North Carolina\u2013Pembroke, Pembroke, NC 28372, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen L.G.","family":"Farizatto","sequence":"additional","affiliation":[{"name":"William C. 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