Abstract
Animal models of Alzheimer’s disease (AD) are invaluable in dissecting the pathogenic mechanisms and assessing the efficacy of potential new therapies. Here, we used the peroxisome proliferator-activated receptor gamma agonist pioglitazone in an attempt to rescue the pathogenic phenotype in adult (12 months) and aged (>18 months) bitransgenic A/T mice that overexpress a mutated human amyloid precursor protein (APPSwe,Ind) and a constitutively active form of transforming growth factor-β1 (TGF-β1). A/T mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone normalized neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort notwithstanding a progressing Aβ pathology. While pioglitazone preserved the constitutive nitric oxide synthesis in the vessel wall, it unexpectedly failed to restore cerebrovascular reactivity in A/T mice and even exacerbated the dilatory deficits. These data demonstrate pioglitazone’s efficacy on selective AD hallmarks in a complex AD mouse model of comorbid amyloidosis and cerebrovascular pathology. They further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.
Highlights
Alzheimer’s disease (AD), the most common form of senile dementia in the elderly, is characterized by increased levels of amyloid-β (Aβ) peptide and neurofibrillary tangles, and by neuroinflammation. It is marked by early decreases in cerebral glucose uptake (CGU) and cerebral blood flow (CBF), and by a cerebrovascular pathology [1]
Pioglitazone normalized neurovascular and neurometabolic coupling responses The CBF response to increased neuronal activity induced by whisker stimulation was significantly reduced in adult (18.7±1.7%; p
peroxisome proliferator-activated receptor-γ (PPARγ) activation may have facilitated the ability of astrocytes to synthesize arachidonic acid derivatives such as vasodilatory epoxyeicosatrienoic acids (EETs) that mediate a large part of the neurovascular coupling response to whisker stimulation [25,40], a response severely affected in both APP and A/T mice [5,41]
Summary
Alzheimer’s disease (AD), the most common form of senile dementia in the elderly, is characterized by increased levels of amyloid-β (Aβ) peptide and neurofibrillary tangles, and by neuroinflammation. It is marked by early decreases in cerebral glucose uptake (CGU) and cerebral blood flow (CBF), and by a cerebrovascular pathology [1]. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist that remains a potential candidate for AD therapy [7,8] This interest was originally sparked by pioglitazone’s ability to cross the blood-brain-barrier (BBB) [9] and subsequent findings of its benefits against multiple features of AD pathology. Further testing of pioglitazone therapy in AD might gain from a thorough examination of its efficacy in a more complex model, such as the A/T mice
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