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P3‐211: TRANSIENT HYPERTENSION‐INDUCED CEREBROVASCULAR STRUCTURAL AND FUNCTIONAL DEFICITS IN TGF344 AD RATS ARE RESCUED BY COMBINATION TREATMENT
Author(s) -
McLaurin JoAnne,
Beckett Tina,
Bazzigaluppi Paolo,
Lai Aaron Y.,
Joo Lewis I.,
Gallagher Denis,
Librach Clifford,
Stefanovic Bojana
Publication year - 2018
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.2018.06.1570
Subject(s) - medicine , vascular dementia , pathophysiology , dementia , cardiology , pathology , disease
Background:Midlife hypertension is a major risk factors for lateonset AD, yet restoration of normotension has very modest effects on risk of dementia. This study aimed to characterize the molecular and pathophysiological mechanisms by which transient hypertension contributes to dementia. Furthermore, our combined therapeutic approach was designed to target AD pathophysiology in combination with vascular injury. Methods:We modeled transient midlife hypertension by administration of L-NAME, a nitric oxide synthase inhibitor, followed by restoration of normotension by cessation of L-NAME administration. A combination of twophoton fluorescence microscopy, biochemistry and immunohistochemistry was used to examine cerebrovascular structure and function. Following return to normotension, scyllo-inositol (SI) treatment was initiated prior to human umbilical cord perivascular cell (HUCPVC) transplantation. Continuous ASL MRI was performed post-L-NAME treatment, and at endpoint to assess the effects of combination treatment on cerebrovascular function. Results: TgAD and nTg rats developed moderate hypertension that returned to normotension 4-weeks post cessation of LNAME. Cerebrovascular damage was greater and sustained in the hypertensive vs. vehicle administered rats. The combined treatment, HUCPVC + SI, rescued the cerebrovascular deficits induced by transient hypertension to a greater extent than either treatment in isolation. We found that in TgAD rats, L-NAME treatment increased cerebrovascular wall hardening and increased deposition of both parenchymal and vascular amyloid; combination treatment reduced only cerebrovascular amyloid Conclusions: Transient hypertension causes sustained cerebrovascular damage in a transgenic model of Alzheimer’s disease and thus multiple drug treatment paradigms may be necessary to address AD with comorbid vascular disease.