Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice

Abstract

Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer’s disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer’s disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer’s disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer’s disease. Graphical abstract

Oleoylethanolamide facilitates PPARα and TFEB signaling and attenuates Aβ pathology in a mouse model of Alzheimer’s disease

“…They are expressed in both peripheral tissues and the CNS [ 8 – 10 ].Through similar signaling mechanisms, the PPARs play critical roles in cellular metabolism and their dysregulation have been linked to multiple diseases such as type 2 diabetes, cancer and Alzheimer’s disease [ 11 – 13 ]. Synthetic PPARα agonists have been shown to provide beneficial effects in AD mouse models by acting on APP processing and Aβ metabolism [ 14 , 15 ], autophagy and lysosomal pathway [ 16 – 18 ], lipid peroxidation [ 19 ], and neuroinflammation [ 20 , 21 ]. PPARα may exert its effect through crosstalk with PPARβ/δ and PPARγ [ 12 ] or with other transcription factors, among them, the transcription factor EB (TFEB).…”

Oleoylethanolamide facilitates PPARa and TFEB signaling and attenuates Ab pathology in a mouse model of Alzheimer’s disease

“…The effect of OEA in feeding regulation has been attributed to its binding to the peroxisome proliferator activated receptor alpha (PPARα) 5,6 , a ligand activated nuclear receptor that, upon dimerization with the retinoid X receptor, acts as a potent transcription factor to activate downstream targets involved in energy homeostasis, lipid metabolism, autophagy, and in ammation 7 . PPARα agonists have been shown to provide bene cial effects in AD mouse models by acting on APP processing and Aβ metabolism 8,9 , autophagy and lysosomal pathway [10][11][12] , and neuroin ammation 13,14 .…”

Intestinal changes in permeability, tight junction and mucin synthesis in a mouse model of Alzheimer's disease

“…Recent findings suggest that disruption of the gut barrier, commonly known as 'leaky gut', is associated with various central nervous system diseases, including AD ( 20 ). A leaky gut allows gut bacteria and their products to enter the bloodstream, which activates the immune system and triggers inflammation ( 21 ); chronic inflammation is associated with the development and progression of AD ( 22 ).…”