Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is the most common causes of dementia accounting for 50-60% of all cases. The pathological hallmarks of AD are the formation of extracellular plaques consisting of amyloid-β protein, intracellular neurofibrillary tangles of hyperphosphorylated tau proteins and presence of chronic neuroinflammation causing progressive decline in memory and cognitive functions. The current therapeutic strategies to improve memory deficits aim at preventing the formation and accumulation of amyloid-β and tau phosphorylation. Beyond the plaque and tangle-related targets, other aspects of pathophysiology including molecular transport mechanism, oxidative damage, inflammation and glucose and lipid metabolism may also provide opportunities to slow down the progression of memory loss. A novel therapeutic approach to the treatment of AD is through the exploration of nuclear receptor agonists, peroxisome proliferator-activated receptors (PPARs), which have been clinically used as antidiabetic and dyslipidemic agents. The findings that PPAR agonists may possess antiamyloidogenic, anti-inflammatory, insulin-sensitizing, and cholesterol-lowering potential suggest that they could be interesting candidates for AD drugs. Through this review, we will discuss the probable pathophysiological mechanisms that may elicit the defending role of these receptors in brains of AD patients.

Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: Possible role of 4-hydroxynonenal (4-HNE)

“…PPARβ/δ seems to works as sensor of oxidative stress, this phenomenon being apparent at 3 mo age in Tg mice, typically characterized by the appearance of oxidative stress, [17][18][19][20][21][22] even though in the present study this event is not correlated with cell death, as apoptotic nuclei are not detected by TUNEL analysis at this age. Therefore, it appears that in the neocortex at 3 mo age, the increased levels of PPAR β/δ and the absence of an increase of 4-HNE adducts protect this brain area from the early perturbation of the redox status.…”

“…Indeed, their involvement in neurodegenerative Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer, Parkinson, and Huntington diseases, is well recognized. [15][16][17][18][19][20][21][22] Even though PPAR β/δ is the most abundant isotype in the developing and adult central nervous system (CNS), [23][24][25] its role in neurodegenerative diseases remains unclear. We have previously demonstrated that PPAR β/δ is crucial for neuronal maturation, and that its expression affects the BDNF signaling pathway.…”

Attenuating effect of lisinopril and telmisartan in intracerebroventricular streptozotocin induced experimental dementia of Alzheimer’s disease type: possible involvement of PPAR-γ agonistic property

“…85,86 Further, PPAR-γ is being considered as a novel target to manage cognitive decline in AD patients. 20,87,88 PPAR-γ agonists significantly reduced spatial memory impairment induced by the amyloid burden, Aβ aggregates, Aβ oligomers, astrocytic and microglia activation. 89 Thus, prevention of the protective effect of lisinopril and telmisartan by BADGE suggests that, in addition to their antioxidative, anti-inflammatory and anticholinestrase activity, these drugs may also be acting through the PPAR-γ pathway and thus providing considerable protection in i.c.v.…”

MK886 Reduces Cerebral Amyloid Angiopathy Severity in TgCRND8 Mice

“…Recently, leukotriene B 4 has been identified as a physiological agonist of peroxisome proliferator-activated receptor-α (PPARα), a member of the nuclear hormone receptor family that regulates the transcription of genes involved in inflammation and lipid metabolism, including apolipoprotein (apo) A-I, apoE and low density lipoprotein receptor-related protein-1 (LRP-1) [9,10]. Activation of PPARs has been shown to upregulate Aβ clearance via apoE and LRP-1, reduce inflammation and lower cholesterol, thereby making them therapeutic candidates for the treatment of AD [11,12]. …”