Amandeep Mann1, Elise Gondard1, Davide Tampellini2, Jorge A T Milsted1, Desiree Marillac1, Clement Hamani3, Suneil K Kalia4, Andres M Lozano5. 1. Krembil Research Institute, Toronto Western Hospital, Toronto, ON, M5T 2S8, Canada. 2. U 1195 Inserm - Université Paris Sud, 80 rue du General Leclerc, 94276, Le Kremlin-Bicêtre, France. 3. Neuroimaging Research Section, Centre for Addictions and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada. 4. Krembil Research Institute, Toronto Western Hospital, Toronto, ON, M5T 2S8, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada. 5. Krembil Research Institute, Toronto Western Hospital, Toronto, ON, M5T 2S8, Canada; Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto, ON, M5S 1A8, Canada. Electronic address: lozano@uhnresearch.ca.
Abstract
BACKGROUND: Alzheimer's disease (AD) is a progressive degenerative disorder that currently remains extremely disabling. Recent work has shown that deep brain stimulation (DBS) has promising effects in AD patients. In parallel to the clinical trials, we investigated the impact of chronic DBS in 3xTg mice, a well-established animal model of AD. METHODS: AD mice were assigned to control (Cont), non-stimulation (NS) and stimulation (DBS) groups, along with age matched wild type controls (WT-Cont). Bilateral electrodes were implanted in the entorhinal cortex to deliver chronic high frequency stimulation for 25 days. Animals were tested in memory behavioral tasks, with post-mortem measurements of pathological markers. RESULTS: We found that chronic DBS in AD mice normalized their impaired performance in the Morris water maze task to that of the WT group in the probe test. In the novel object and novel place preference tasks, AD-DBS mice spent more time at the novel object and novice location compared to AD-NS mice. These cognitive improvements in AD-DBS mice were associated with DBS induced increased neurogenesis in the dentate gyrus, a significant reduction in β-amyloid plaques, a reduction in CA-1 cellular β-amyloid-42 levels, decreased cortical total-tau and phosphorylated-tau, along with decreased hippocampal total-tau. CONCLUSION: Overall, we show that chronic DBS of the entorhinal cortex in AD mice improves both memory and AD specific pathological markers. These results support further testing of DBS as a potential treatment in AD patients.
BACKGROUND:Alzheimer's disease (AD) is a progressive degenerative disorder that currently remains extremely disabling. Recent work has shown that deep brain stimulation (DBS) has promising effects in ADpatients. In parallel to the clinical trials, we investigated the impact of chronic DBS in 3xTg mice, a well-established animal model of AD. METHODS:ADmice were assigned to control (Cont), non-stimulation (NS) and stimulation (DBS) groups, along with age matched wild type controls (WT-Cont). Bilateral electrodes were implanted in the entorhinal cortex to deliver chronic high frequency stimulation for 25 days. Animals were tested in memory behavioral tasks, with post-mortem measurements of pathological markers. RESULTS: We found that chronic DBS in ADmice normalized their impaired performance in the Morris water maze task to that of the WT group in the probe test. In the novel object and novel place preference tasks, AD-DBS mice spent more time at the novel object and novice location compared to AD-NSmice. These cognitive improvements in AD-DBS mice were associated with DBS induced increased neurogenesis in the dentate gyrus, a significant reduction in β-amyloid plaques, a reduction in CA-1 cellular β-amyloid-42 levels, decreased cortical total-tau and phosphorylated-tau, along with decreased hippocampal total-tau. CONCLUSION: Overall, we show that chronic DBS of the entorhinal cortex in ADmice improves both memory and AD specific pathological markers. These results support further testing of DBS as a potential treatment in ADpatients.
Authors: Elise Gondard; Lucy Teves; Lihua Wang; Chris McKinnon; Clement Hamani; Suneil K Kalia; Peter L Carlen; Michael Tymianski; Andres M Lozano Journal: J Neurosci Date: 2019-01-29 Impact factor: 6.167
Authors: Emily A Mankin; Zahra M Aghajan; Peter Schuette; Michelle E Tran; Natalia Tchemodanov; Ali Titiz; Güldamla Kalender; Dawn Eliashiv; John Stern; Shennan A Weiss; Dylan Kirsch; Barbara Knowlton; Itzhak Fried; Nanthia Suthana Journal: Brain Stimul Date: 2020-12-03 Impact factor: 8.955
Authors: Anton Fomenko; Darrin J Lee; Chris McKinnon; Eun Jung Lee; Mitchell L de Snoo; Elise Gondard; Clemens Neudorfer; Clement Hamani; Andres M Lozano; Lorraine V Kalia; Suneil K Kalia Journal: Front Neurosci Date: 2020-05-12 Impact factor: 4.677
Authors: Qian Liu; Yihang Jiao; Weijian Yang; Beiyao Gao; Daniel K Hsu; Jan Nolta; Michael Russell; Bruce Lyeth; Theodore P Zanto; Min Zhao Journal: Alzheimers Res Ther Date: 2020-07-23 Impact factor: 8.823