Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer's disease mouse model

Abstract

The response of the lysosomes, the waste clearance machinery of the cell, to different environmental stimuli is coordinated by a gene network with a master regulator Transcription factor EB (TFEB) at the core. Disruption of multiple facets of the lysosomal and autophagic network has been linked to various neurodegenerative and lysosomal storage disorders, making TFEB an attractive therapeutic target to rescue or augment lysosomal function under pathological scenario. In this study, we demonstrate that cinnamic acid, a naturally occurring plant-based product, induces lysosomal biogenesis in mouse primary brain cells via upregulation of TFEB. We delineate that cinnamic acid activates the nuclear hormone receptor PPARα to transcriptionally upregulate TFEB and stimulate lysosomal biogenesis. Moreover, using in-silico and biochemical approaches we established that cinnamic acid serves as a potent ligand for peroxisome proliferator-activated receptor α (PPARα). Finally, cinnamic acid treatment in male and female 5× Familial Alzheimer’s disease (5XFAD) mice remarkably reduced cerebral amyloid-beta plaque burden and improved memory via PPARα. Therefore, stimulation of lysosomal biogenesis by cinnamic acid may have therapeutic implications for treatment of Alzheimer’s disease and other lysosomal disorders originating from accumulation of toxic protein aggregates.

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

“…These people were characterized by lower Aβ 1-42 concentration, in comparison to age related, non-treated healthy humans (control group) [53]. The last data published by Chandra et al [54] and Chandra and Pahan [55] demonstrated that activators of PPAR-α (cinnamic acid and gemfibrozil) decrease amyloid plaque in the hippocampus and cortex in the animal model of AD (5XFAD). Moreover, they decrease neuroinflammation and thus microglia and astrocytes activation and improve spatial learning and cognition function.…”

Targeting Aggrephagy for the Treatment of Alzheimer’s Disease

“…5xFAD mice treatment with aspirin and cinnamic acid activates TFEB gene promotor PPARGC1α and increased TFEB expression level. Elevated TFEB promotes lysosomal biogenesis and reduces Aβ plaque burden [178,179].…”

PPARα serves as a new receptor of aspirin for neuroprotection

“…We have demonstrated that PPARα displays a strong affinity toward compounds with long‐aliphatic side chains such as very long‐chain fatty acids including 9‐octadecenamide and hexadecanamide (Roy, Kundu, et al, ). In addition, PPARα also exhibits strong affinity toward small molecules such as statins and cinnamic acid (Chandra, Roy, Jana, & Pahan, ; Roy, Jana, Kundu, et al, ; Roy, Kundu, et al, ). This extremely diverse selection of ligands is achieved due to the amphipathic nature of LBD of PPARα.…”