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Increasing evidence suggests that phosphorylated Tau and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline, in patients with AD. In the current study, we investigated whether a partial reduction of Drp1 protect neurons from phosphorylated Tau-induced mitochondrial and synaptic toxicities in AD progression. We crossed Drp1+\/\u2212 mice with Tau transgenic mice (P301L line) and created double mutant (TauXDrp1+\/\u2212) mice. Using real-time RT-PCR, immunoblotting and immunostaining analyses, we measured mRNA expressions and protein levels of genes related to the mitochondrial dynamics\u2014Drp1 and Fis1 (fission), Mfn1, Mfn2 and Opa1 (fusion), CypD (matrix), mitochondrial biogenesis\u2014Nrf1, Nrf2, PGC1\u03b1 and TFAM and synaptic\u2014synaptophysin, PSD95, synapsin 1, synaptobrevin 1, neurogranin, GAP43 and synaptopodin in brain tissues from 6-month-old Drp1+\/\u2212, Tau, TauXDrp1+\/\u2212 and wild-type mice. Using biochemical and immunoblotting methods, mitochondrial function and phosphorylated Tau were measured. Decreased mRNA and protein levels of fission and matrix and increased levels of fusion, mitochondrial biogenesis, and synaptic genes were found in 6-month-old TauXDrp1+\/\u2212 mice relative to Tau mice. Mitochondrial dysfunction was reduced in TauXDrp1+\/\u2212 mice relative to Tau mice. Phosphorylated Tau found to be reduced in TauXDrp1+\/\u2212 mice relative to Tau mice. These findings suggest that a partial reduction of Drp1 decreases the production of phosphorylated Tau, reduces mitochondrial dysfunction, and maintains mitochondrial dynamics, enhances mitochondrial biogenesis and synaptic activity in Tau mice. Findings of this study may have implications for the development of Drp1 based therapeutics for patients with AD and other tauopathies.<\/jats:p>","DOI":"10.1093\/hmg\/ddw312","type":"journal-article","created":{"date-parts":[[2016,9,16]],"date-time":"2016-09-16T03:14:00Z","timestamp":1473995640000},"page":"4881-4897","source":"Crossref","is-referenced-by-count":178,"title":["Reduced dynamin-related protein 1 protects against phosphorylated Tau-induced mitochondrial dysfunction and synaptic damage in Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"25","author":[{"given":"Ramesh","family":"Kandimalla","sequence":"first","affiliation":[{"name":"1Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Manczak","sequence":"additional","affiliation":[{"name":"1Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Fry","sequence":"additional","affiliation":[{"name":"1Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeguvapalli","family":"Suneetha","sequence":"additional","affiliation":[{"name":"1Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Sesaki","sequence":"additional","affiliation":[{"name":"2Cell Biology Department, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, 109 Hunterian, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Hemachandra","family":"Reddy","sequence":"additional","affiliation":[{"name":"1Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA,"},{"name":"3Cell Biology & Biochemistry Department"},{"name":"4Neuroscience & Pharmacology Department"},{"name":"5Neurology Departmednt"},{"name":"6Speech, Language and Hearing Sciences Departments, Texas Tech University Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, TX 79430, USA"},{"name":"7Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, 6630\u2009S. Quaker Suite E, MS 7495, Lubbock, TX 79413, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,15]]},"reference":[{"key":"2023080907311993200_ddw312-B1","doi-asserted-by":"crossref","first-page":"2973","DOI":"10.1093\/hmg\/dds128","article-title":"Mitochondria-targeted catalase reduces abnormal APP processing, amyloid beta production and BACE1 in a mouse model of Alzheimer's disease: implications for neuroprotection and lifespan extension","volume":"21","author":"Mao","year":"2012","journal-title":"Hum. Mol. Genet"},{"key":"2023080907311993200_ddw312-B2","doi-asserted-by":"crossref","first-page":"340","DOI":"10.2174\/1567205011666140331161027","article-title":"CSF ubiquitin as a specific biomarker in Alzheimer's disease","volume":"11","author":"Kandimalla","year":"2014","journal-title":"Curr. 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