PPAR-α agonist regulates amyloid-β generation via inhibiting BACE-1 activity in human neuroblastoma SH-SY5Y cells transfected with APPswe gene

Abstract

Alzheimer's disease is a neuroinflammatory disease and is the most common cause of dementia in the elderly. Studies have shown the beneficial effects of the peroxisome proliferator-activated receptor alpha (PPAR-α) agonists on the treatment of neuroinflammatory diseases. The aim of the present study is to examine the ability of GW7647 (a PPAR-α agonist) to regulate amyloid precursor protein (APP) amyloidogenic processing in human neuroblastoma SH-SY5Y cells transfected with APPswe gene. After administration of GW7647 for 24 h, the levels of APP, soluble APPβ (sAPPβ), and presenilin 1 (PS-1) were assessed by Western blot. Cellular culture medium levels of amyloid-β 42 (Aβ42) were analyzed by ELISA, and the activity of beta-site APP cleaving enzyme 1 (BACE-1) was measured by fluorometric assay. We found that GW7647 decreased the expression of sAPPβ and the activity of BACE-1, and also reduced Aβ42 release. However, GW7647 did not modify the levels of APP and PS-1. Furthermore, LY294002, the phosphoinositide 3-kinase (PI3-K) inhibitor, reversed the effects of GW7647 on the BACE-1 activity and the levels of sAPPβ and Aβ42. Our data demonstrate that GW7647 may reduce Aβ production via inhibiting BACE-1 activity, and this may involve in PI3-K pathway.

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

“…Very interestingly, recent studies from our group also demonstrated that BR297 efficiently improved neuroblastoma cell bioenergetics by increasing the cellular ATP level and mitochondrial respiration under normal/physiological situations . Consistently, BR297 treatment, which reduced ROS levels, as well as ameliorated mitochondrial respiration and cell survival, was also more effective than AP with respect to preventing oxidative stress‐evoked death of the APP‐transfected neuroblastoma cells that represent a relevant and reliable cell model for the investigation of physio‐pathological mechanisms involved in AD . We have also found that our 3α‐analogue BR351 (O‐allyl‐AP), which strongly promoted the proliferation and protection of neural stem cells against β‐amyloid‐induced death, only slightly stimulated mitochondrial activities .…”

“…Because the key neuroendocrine and neuroactive neurosteroid AP exerts pleiotropic actions, including cell proliferation-promoting, neurogenic and neuroprotective effects, its use in the development of targeted therapeutic strategies remains complex. [4][5][6][7][8][9][10][11][12][13][14][15][16]23,35,36,56,57 Therefore, we decided to synthesise AP analogues with the aim of identifying compounds that may have higher efficacy and/or better [65][66][67][68][69][70] We have also found that our 3αanalogue BR351 (O-allyl-AP), which strongly promoted the proliferation and protection of neural stem cells against β-amyloid-induced death, only slightly stimulated mitochondrial activities. 58,71 Therefore, it appears that the subtle structural difference between BR351 and BR297 is sufficient to generate selective activity profiles allowing the possibility of developing a BR351-or BR297-based therapeutic strategy adapted to the pathological conditions that require either neurogenic and neuroprotective effects or only a selective action to protect nerve cells against death without promoting cell proliferation.…”

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

“…Another study reveals, that agonist of PPAR-α (WY14643) increases ADAM 10 (α secretase) expression in hippocampal neurons, however neurons lacking PPAR-α [49]. The other data of Zhang et al [50] demonstrated, that PPAR-α agonist (GW7647) regulates amyloid β (Aβ) generation by inhibition of BACE-1 activity. Moreover, it was observed that agonist of PPAR-α receptor (GW7647) which decreased the expression of sAPPβ and the activity of BACE-1 and Aβ 1-42 level in cell model of AD had no effect on the level of APP and Preseniline-1 (PS1).…”

Investigating piwi‐interacting RNA regulome in human neuroblastoma

“…37 After that, we searched for the presence of any existing upstream regulator of these TFs and found 17 TFs without any such regulators. The other two TFs, EIF2AK2, a regulator of PI3/AKT associated factors and PPARA, a regulator of genes involved in cell growth and proliferation have been found to have lower expression in NB, [72][73][74][75] which can also be possibly due to multiple piRNAs targeting these TFs as upstream regulators. Of these, two TFs, BRCA1, a well-known factor for controlling DNA damage, double-strand break and transcriptional regulation and HDAC2, the epigenetic regulator of various cancer associated genes are recently detected to be aberrantly expressed in NB.…”

“…[68][69][70][71] We assume that the aberrant expression of these targets in NB is probably the result of targeting by multiple piRNAs. The other two TFs, EIF2AK2, a regulator of PI3/AKT associated factors and PPARA, a regulator of genes involved in cell growth and proliferation have been found to have lower expression in NB, [72][73][74][75] which can also be possibly due to multiple piRNAs targeting these TFs as upstream regulators.…”