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

Abstract

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD).Using aged (ϳ16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-␤ (A␤) 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 A␤ levels or A␤ 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.

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

“…Therapeutic candidates in this class include peroxisome proliferator-activated receptor-γ [73,74]. Preclinically, pioglitazone restored cerebrovascular function, reduced oxidative stress, and increased mitochondrial respiration [75][76][77]. Pioglitazone was initially tested in the human neuron-like NT2 cell line, where it induced mitochondrial biogenesis, increased mtDNA content and subunit proteins, and reduced mitochondrial oxidative damage [78].…”

“…Pioglitazone was initially tested in the human neuron-like NT2 cell line, where it induced mitochondrial biogenesis, increased mtDNA content and subunit proteins, and reduced mitochondrial oxidative damage [78]. Rosiglitazone stimulated neuronal mitochondrial biogenesis and reduced memory deficits in mouse models of AD [75][76][77]. A small clinical trial of 32 patients with mild AD showed significant improvements with pioglitazone treatment on both the AD Assessment Scale-Cognitive subscale scores and Wechsler Memory Scale-Revised Logical Memory Performance tests [92,93].…”

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…In the experiment on APP tg mice, pioglitazone counteracted cerebral oxidative stress, glial activation, and, partly, cholinergic denervation and completely normalized the cerebral blood flow and glucose uptake responses to increased neuronal activity, but it failed to improve spatial memory (Nicolakakis et al 2008). An acute 7 day oral pioglitazone treatment of 10-month-old APPV717I mice attenuated astrogliosis in the hippocampus and cortex and reduced the level of soluble Abeta1-42 peptide, in addition to reduction of the expression of the proinflammatory enzymes COX2 and inducible NOS, and decrement of beta-secretase-1 (BACE1) mRNA and protein levels (Heneka et al 2005).…”

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

“…Neurovascular coupling dysfunction of AD has been replicated in experimental studies showing that in mouse models of AD, neurovascular coupling is also significantly impaired (Rancillac et al 2012;Shin et al 2007;Royea et al 2017), at least in part, due to enhanced oxidative stress (Nicolakakis et al 2008;Park et al 2008;Park et al 2005) arising from mitochondrial dysfunction and inflammation (Lacoste et al 2013;Ongali et al 2014). Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008). Due to the increased realization that understanding of the mechanisms underlying neurovascular dysfunction is critical for developing novel therapeutic interventions to prevent or treat AD, there is an increasing need in many laboratories to adapt methodologies to investigate neurovascular coupling responses in mouse models of aging and AD (Lacoste et al 2013;Ongali et al 2014;Papadopoulos et al 2016;Hamel et al 2016;Nicolakakis and Hamel 2011;Papadopoulos et al 2014).…”

“…Vascular dysregulation in AD includes deficiencies in cerebrovascular reactivity, CBF, and neurovascular coupling responses (Girouard and Iadecola 2006;Gorelick et al 2011;Hock et al 1997;Rombouts et al 2000). Neurovascular coupling dysfunction of AD has been replicated in experimental studies showing that in mouse models of AD, neurovascular coupling is also significantly impaired (Rancillac et al 2012;Shin et al 2007;Royea et al 2017), at least in part, due to enhanced oxidative stress (Nicolakakis et al 2008;Park et al 2008;Park et al 2005) arising from mitochondrial dysfunction and inflammation (Lacoste et al 2013;Ongali et al 2014). Importantly, recent evidence suggests that pharmacological interventions that rescue functional hyperemia result in improved cognitive function in mice with AD pathologies (Tong et al 2012;Nicolakakis et al 2008).…”