Intact memory in TGF-β1 transgenic mice featuring chronic cerebrovascular deficit: recovery with pioglitazone.
The roles of chronic brain hypoperfusion and transforming growth factor-beta 1 (TGF-β1) in Alzheimer's disease (AD) are unresolved. We investigated the interplay between TGF-β1, cerebrovascular function, and cognition using transgenic TGF mice featuring astrocytic TGF-β1 overexpression. We further assessed the impact of short, late therapy in elderly animals with the antioxidant N-acetyl-L-cysteine (NAC) or the peroxisome proliferator-activated receptor-γ agonist pioglitazone. The latter was also administered to pups as a prophylactic 1-year treatment. Elderly TGF mice featured cerebrovascular dysfunction that was not remedied with NAC. In contrast, pioglitazone prevented or reversed this deficit, and rescued the impaired neurovascular coupling response to whisker stimulation, although it failed to normalize the vascular structure. In aged TGF mice, neuronal and cognitive indices--the stimulus-evoked neurometabolic response, cortical cholinergic innervation, and spatial memory in the Morris water maze--were intact. Our findings show that impaired brain hemodynamics and cerebrovascular function are not accompanied by memory impairment in this model. Conceivably in AD, they constitute aggravating factors against a background of aging and underlying pathology. Our data further highlight the ability of pioglitazone to protect the cerebrovasculature marked by TGF-β1 increase, aging, fibrosis, and antioxidant resistance, thus of high relevance for AD patients.
Nicolakakis
Nektaria
N
Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada.
Aboulkassim
Tahar
T
Aliaga
Antonio
A
Tong
Xin-Kang
XK
Rosa-Neto
Pedro
P
Hamel
Edith
E
D000375:Aging / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D002560:Cerebrovascular Circulation / Q000187:drug effects; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology*; D003071:Cognition / Q000502:physiology; D005355:Fibrosis / Q000473:pathology; D019788:Fluorodeoxyglucose F18; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D017078:Laser-Doppler Flowmetry; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020768:Middle Cerebral Artery / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000503:physiopathology; D000077205:Pioglitazone; D019275:Radiopharmaceuticals; D045162:Thiazolidinediones / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D014738:Vibrissae / Q000502:physiology
D000975:Antioxidants; D007004:Hypoglycemic Agents; D019275:Radiopharmaceuticals; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D019788:Fluorodeoxyglucose F18; D000077205:Pioglitazone