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P3‐318: The effect of aerobic exercise on fall risk reduction among older adults with mild vascular cognitive impairment
Author(s) -
Falck Ryan S.,
Brinke Lisanne,
Robin Hsiung Ging-Yuek,
Eng Janice J.,
Munkacsy Michelle,
Cheung Winnie,
Jacova Claudia,
Davis Jennifer,
Liu-Ambrose Teresa,
Dao Elizabeth
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.1692
Subject(s) - medicine , physical therapy , randomized controlled trial , cognitive impairment , cognition , physical medicine and rehabilitation , psychiatry
must be exported to the peripheral circulation. The conversion to 24-hydroxycholesterol, (24-0Hchol) by the key neuronal enzyme cholesterol 24-hydroxylase (CYP46A1), represents the main mechanism by which cholesterol in excess is eliminated from the brain. Methods: Since there is currently no molecule able to increase CYP46A1 activity and cross the BBB, we propose to directly overexpress CYP46A1 by administrating in the brain an AAV vector carrying the CYP46A1 cDNA. In order to find the optimal vector, we compared CYP46A1 overexpression in the hippocampus of C57Bl6/J mice by mean of stereotactic injection of several AAV serotypes: AAV5, AAV9 and AAVrh10. Results: Immunohistochemistry and western-blot revealed that hippocampal overexpression of CYP46A1 by means of AAV9 or AAVrh10 had similar patterns of expression. Moreover, it resulted in a more neuronal widespread distribution and robust CYP46A1 expression compared to AAV5. Western-blot analysis also revealed that CYP46A1 expression was w3-fold higher with AAV9 and AAVrh10 compared to AAV5. The functionality of these vectors was assessed by mass spectroscopy that demonstrated significant increase in 24-0Hchol levels in mouse hippocampus transduced with AAV9 and AAVrh10 compared to AAV5. In a therapeutic angle, we overexpressed CYP46A1 (or a control vector) by mean of an AAV9 in the hippocampus of 2.5month-old (after onset of plaques formation) APP/PS1 knock-in mice. Four months post-injection we observed that CYP46A1 overexpression induced a significant decrease in Ab-peptides and mild reduction of amyloid plaques. Furthermore, levels of GFAP and SMI-25 proteins were decreased suggesting reduced inflammation. This was complemented in an alternative mouse model of AD (APP23). CYP46A1 was overexpressed in the hippocampus of 3-months-old APP23 mice. Behavioral assessment using the Morris-water-maze and the openfield tests revealed that CYP46A1 overexpression rescued memory deficits as well as ameliorated spontaneous behavior, nine months post-injection. Conclusions:These data strongly suggest CYP46A1 as a relevant target for AD.