Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubuleassociated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.

G protein-coupled receptor 81 (GPR81) inhibition attenuated ischemic neuronal death. Lactate may aggravate ischemic brain injury by activating GPR81. GPR81 antagonism might be a novel therapeutic strategy for the treatment of cerebral ischemia.

Aim Mitochondrial autophagy (mitophagy) clears damaged mitochondria and attenuates ischemic neuronal injury. Urolithin A (Uro‐A) activates mitophagy in mammal cells and Caenorhabditis elegans. We explored neuroprotection of Uro‐A against ischemic neuronal injury. Methods Mice were subjected to middle cerebral artery occlusion. The brain infarct and neurological deficit scores were measured. The N2a cells and primary cultured mice cortical neurons were subjected to oxygen‐glucose deprivation and reperfusion (OGD/R). Uro‐A was incubated during OGD/R, and cell injury was determined by MTT and LDH. Autophagosomes were visualized by transfecting mCherry‐microtubule‐associated protein 1 light chain 3 (LC3). The protein levels of LC3‐II, p62, Translocase Of Inner Mitochondrial Membrane 23 (TIMM23), and cytochrome c oxidase subunit 4 isoform 1 (COX4I1) were detected by Western blot. The ER stress markers, activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), were determined by reverse transcription‐polymerase chain reaction (RT‐PCR). Results Urolithin A alleviated OGD/R‐induced injury in N2a cells and neurons and reduced ischemic brain injury in mice. Uro‐A reinforced ischemia‐induced autophagy. Furthermore, Uro‐A‐conferred protection was abolished by 3‐methyladenine, suggesting the requirement of autophagy for neuroprotection. However, mitophagy was not further activated by Uro‐A. Instead, Uro‐A attenuated OGD/R‐induced ER stress, which was abolished by 3‐methyladenosine. Additionally, neuroprotection was reversed by ER stress inducer. Conclusion Urolithin A protected against ischemic neuronal injury by reinforcing autophagy rather than mitophagy. Autophagy activation by Uro‐A attenuated ischemic neuronal death by suppressing ER stress.

Summary Axonal mitochondrial quality is essential for neuronal health and functions. Compromised mitochondrial quality, reflected by loss of membrane potential, collapse of ATP production, abnormal morphology, burst of reactive oxygen species generation, and impaired Ca 2+ buffering capacity, can alter mitochondrial transport. Mitochondrial transport in turn maintains axonal mitochondrial homeostasis in several ways. Newly generated mitochondria are anterogradely transported along with axon from soma to replenish axonal mitochondrial pool, while damaged mitochondria undergo retrograde transport for repair or degradation. Besides, mitochondria are also arrested in axon to quarantine damages locally. Accumulating evidence suggests abnormal mitochondrial transport leads to mitochondrial dysfunction and axon degeneration in a variety of neurological and psychiatric disorders. Further investigations into the details of this process would help to extend our understanding of various neurological diseases and shed light on the corresponding therapies.

Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO 2 for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO 2 for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO 3 significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen-glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis. Keywords: acidosis treatment; cerebral ischemia; mPTP; neuroprotection INTRODUCTION Ischemic postconditioning, a neuroprotective strategy for ischemic stroke, has attracted much attention over the past 7 years. It is defined as a series of cycles of brief reperfusion and ischemia applied at the onset of reperfusion, which can mobilize the brain's own endogenous adaptive mechanisms and limit the extent of reperfusion injury. In 2006, Zhao et al 1 first reported that ischemic postconditioning reduces infarct volume in experimental cerebral ischemia and reperfusion (I/R) injury. Since then, its cerebral protective effects have been confirmed in several distinct ischemia models.2-5 However, the clinical application of ischemic postconditioning may be limited because of the difficulties in achieving well-controlled interruptions of reperfusion and the risks associated with these manipulations.6 Hypoxia, as a key component of ischemia, is a feasible treatment for ischemic stroke in theory. Surprisingly, we have recently found that an early application of hypoxic postconditioning after reperfusion does not induce neuroprotection against cerebral I/R injury.7 Thus, attempts should be undertaken to identify the other key factors, which are responsible for the protection afforded by ischemic postconditioning, and to develop a new therapeutic strategy, which is relatively safe and practical.Acidosis is another key component of ischemia besides hypoxia and glucose depletion. Extracellular pH can fall...