Amyloid ␤ (A␤) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A␤ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A␤ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38␣ MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38␣ MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A␤ generation in the AD mouse brain. Inhibition of p38␣ MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38␣ MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38␣ MAPK plays a critical role in the regulation of BACE1 degradation and A␤ generation in AD pathogenesis. Alzheimer disease (AD)2 is pathologically characterized by the extracellular deposits of amyloid ␤ peptide (A␤). A␤ injures neurons in the neocortex and limbic system directly (1) and indirectly by triggering microglial release of various neurotoxic inflammatory mediators, including cytokines (tumor necrosis factor-␣ and interleukin-1␤ (IL-1␤)) and reactive oxygen species (2). A␤ is generated after serial digestion of Alzheimer amyloid precursor protein (APP) by the membrane-anchored ␤-site APP-cleaving enzyme (BACE1, ␤-secretase) and ␥-secretase (3). It has been observed that knock-out of BACE1 or administration of the BACE1 inhibitor dramatically decreases A␤ levels in the brain and attenuates behavioral and electrophysiological deficits in APP-transgenic mice (4 -6). Thus, extensive investigations have focused on the direct inhibition of BACE1 to reduce A␤ load in the AD brain; however, these studies have unfortunately not yet led to any efficacious therapy for AD patients due to the various physiological roles of BACE1 (7). Using alternative methods to inhibit BACE1 might be a preferable investigative approach.Inflammatory activation might lead to up-regulation of neuronal BACE1 expression in the AD brain, as NF-B signaling enhances (8), and PPAR␥ activation suppresses (9), the activity of bace1 gene promoter. Accumulating evidence has shown that posttranslational modification of BACE1 is extremely important for the activity, intracellular trafficking, and lysosomal degradation of BACE1. For example, phosphorylation of BACE1 at Thr-252 by p25/Cdk5 increases the secretase activity (10), and phosphorylation at Ser-498 facilitates retrograde transport of BACE1 from endosomes to the trans-Golgi network (11). Ubiquitination at Lys-501 targets BACE1 to late endosomes/lysosomes for degradation (12). Finally, bisecting N-acetylglucosamine modification blocks delivery of BACE1 to lysosomes (13).p38 mitogen-activated protei...

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Alzheimer’s disease (AD) is characterized by intracellular neurofibrillary tangles. The primary component, hyperphosphorylated Tau (p-Tau), contributes to neuronal death. Recent studies have shown that autophagy efficiently degrades p-Tau, but the mechanisms modulating autophagy and subsequent p-Tau clearance in AD remain unclear. In our study, we first analyzed the relationship between the inflammatory activation and autophagy in brains derived from aged mice and LPS-injected inflammatory mouse models. We found that inflammatory activation was essential for activation of autophagy in the brain, which was neuronal ATG5-dependent. Next, we found that autophagy in cultured neurons was enhanced by LPS treatment of cocultured macrophages. In further experiments designed to provoke chronic mild stimulation of TLR4 without inducing obvious neuroinflammation, we gave repeated LPS injections (i.p., 0.15 mg/kg, weekly for 3 mo) to transgenic mice overexpressing human Tau mutant (P301S) in neurons. We observed significant enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function. In summary, these results show that neuroinflammation promotes neuronal autophagy and that chronic mild TLR4 stimulation attenuates AD-related tauopathy, likely by activating neuronal autophagy. Our study displays the beneficial face of neuroinflammation and suggests a possible role in the treatment of AD patients.