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The Journal of Neuroscience, September 10, 2008, 28(37):9287-9296; doi:10.1523/JNEUROSCI.3348-08.2008

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Neurobiology of Disease
Complete Rescue of Cerebrovascular Function in Aged Alzheimer's Disease Transgenic Mice by Antioxidants and Pioglitazone, a Peroxisome Proliferator-Activated Receptor Agonist

Nektaria Nicolakakis,¹ Tahar Aboulkassim,¹ Brice Ongali,¹ Clotilde Lecrux,¹ Priscilla Fernandes,¹ Pedro Rosa-Neto,^2,3 Xin-Kang Tong,¹ and Edith Hamel¹

¹Laboratory of Cerebrovascular Research, ²Brain Imaging Centre, Montréal Neurological Institute, and ³Douglas Hospital Research Centre, McGill University, Montréal, Québec, Canada H3A 2B4

Correspondence should be addressed to Dr. Edith Hamel, Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4. Email: edith.hamel{at}mcgill.ca

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged (16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-β (Aβ) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Aβ levels or Aβ plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.

Key words: amyloid-β; PPAR; memory; cholinergic; oxidative stress; cerebral blood vessels

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Received April 22, 2008; accepted Aug. 9, 2008.

Correspondence should be addressed to Dr. Edith Hamel, Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4. Email: edith.hamel{at}mcgill.ca

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				K. L. Lanctot, R. D. Rajaram, and N. Herrmann Review: Therapy for Alzheimer's disease: how effective are current treatments? Therapeutic Advances in Neurological Disorders, May 1, 2009; 2(3): 163 - 180. [Abstract] [PDF]

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