Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

Abstract

Amyloid precursor protein (APP) derivative β-amyloid (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by β-secretase and γ-secretase generates Aβ. Conversely, the α-secretase "a disintegrin and metalloproteinase" 10 (ADAM10) cleaves APP within the eventual Aβ sequence and precludes Aβ generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPARα, but not PPARβ or PPARγ, decreases the expression of Adam10; and that lentiviral overexpression of PPARα restored ADAM10 expression in Ppara −/− neurons. Gemfibrozil, an agonist of PPARα, induced the recruitment of PPARα:retinoid x receptor α, but not PPARγ coactivator 1α (PGC1α), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the α-secretase, as determined by augmented soluble APPα and decreased Aβ production. Accordingly, Ppara −/− mice displayed elevated SDS-stable, endogenous Aβ and Aβ 1-42 relative to wild-type littermates, whereas 5XFAD mice null for PPARα (5X/α −/− ) exhibited greater cerebral Aβ load relative to 5XFAD littermates. These results identify PPARα as an important factor regulating neuronal ADAM10 expression and, thus, α-secretase proteolysis of APP.is the most prevalent neurodegenerative disease. Although the precise physiologic changes that trigger development of AD remain unknown, abnormal metabolism of the type 1 transmembrane amyloid precursor protein (APP) into amyloid-β (Aβ) plays a causative role in AD (1). Sequential proteolytic processing of APP by the aspartic proteases β-secretase 1 (BACE1) and γ-secretase (reviewed in ref.2) at ectodomain and intramembrane sites, respectively, generates pathogenic Aβ fragments between residues 36 and 43. Conversely, juxtamembrane cleavage of APP between K16/L17 residues by α-secretase precludes Aβ generation and results in clearance of APP (3).Several proteases have been suggested as AD-relevant α-secretases, many of which belong to the "a disintegrin and metalloproteinase" (ADAM) Zn 2+ sheddase family (reviewed in ref. 4) and include ADAM9, ADAM10, and ADAM17. However, ADAM10 has emerged as the constitutive and inducible APP α-secretase in neurons (5). Of note, ADAM9 and ADAM17 do not recover α-secretase proteolysis of APP in the absence of ADAM10 (5), neuron-specific overexpression of ADAM10 decreases Aβ load in a mouse model of AD (6), and impaired ADAM10 trafficking to the synapse generates a model of sporadic AD (7). Similarly, human studies have observed deficits in ADAM10 expression (8), trafficking (9), and activity (10) in AD. Therefore, dysregulation of ADAM10 may play a significant role in the establishment of Aβ pathology. However, little is known about the genetic regulation of ADAM10....

Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-β

“…ChIP assays were performed using a kit (Millipore) as described earlier (21, 22). Briefly, after 3 h of stimulation, cells were fixed by adding formaldehyde, and cross-linked adducts were resuspended and sonicated.…”

“…For immunofluorescence staining (21, 22), rabbit polyclonal anti-TGFβ (1:100) and goat polyclonal anti-Iba1 (1:100) (Supplementary Table 1) were used. The samples were mounted and observed under an Olympus IX81 fluorescence microscope.…”

Identification and characterization of PPARα ligands in the hippocampus

“…However, recently we have shown that PPARα also plays an important role in the modulation of synaptic function in hippocampus via transcriptional upregulation of CREB 6–8 . It has been also delineated that activation of PPARα in hippocampal neurons leads to the increase in ADAM10 transcription and subsequent non-amyloidogenic proteolysis of APP 9 . These reports highlight a lipid-independent role of PPARα in controlling brain function.…”

PPARα in lysosomal biogenesis: A perspective

“…Although gemfibrozil, marketed as ‘Lopid’, is an agonist of PPARα and a FDA-approved drug for hyperlipidemia [23,24], it has been shown to have multiple beneficial effects [25-30]. The ability of gemfibrozil to cross blood-brain-barrier (BBB) has already been documented [31].…”