ABSTRACT
Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.
Subject(s)
Autistic Disorder/genetics , Cell Proliferation/genetics , GABAergic Neurons/metabolism , Interneurons/metabolism , Neural Stem Cells/metabolism , Neurogenesis/genetics , TOR Serine-Threonine Kinases/metabolism , Ubiquitin-Protein Ligases/genetics , Animals , Autistic Disorder/metabolism , Autophagy/drug effects , Autophagy/genetics , Behavior, Animal/drug effects , Behavior, Animal/physiology , Clonazepam/pharmacology , GABA-A Receptor Agonists/pharmacology , GABAergic Neurons/drug effects , Interneurons/drug effects , Mice , Mice, Knockout , Neural Stem Cells/drug effects , Neurogenesis/drug effects , Proteasome Endopeptidase Complex/metabolism , RGS Proteins/metabolismABSTRACT
Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer's disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+, Parvalbumin+, Calretinin+, and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-ß accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy.
Subject(s)
Alzheimer Disease/surgery , Cognitive Dysfunction/surgery , GABAergic Neurons/transplantation , Interneurons/transplantation , Neural Stem Cells/transplantation , Alzheimer Disease/genetics , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Animals , Cognition/physiology , Cognitive Dysfunction/physiopathology , Disease Models, Animal , Maze Learning/physiology , Mice , Mice, Transgenic , Presenilin-1/geneticsABSTRACT
Sphingolipids emerge as essential modulators in the etiology of Alzheimer's disease (AD) with unclear mechanisms. Elevated levels of SM synthase 1 (SMS1), which catalyzes the synthesis of SM from ceramide and phosphatidylcholine, have been observed in the brains of Alzheimer's disease (AD), where expression of ß-site APP cleaving enzyme 1 (BACE1), a rate limiting enzyme in amyloid-ß (Aß) generation, are upregulated. In the present study, we show knockdown of SMS1 via andeno associated virus (serotype 8, AAV8) in the hippocampus of APP/PS1 transgenic mice, attenuates the densities of Aß plaques, neuroinflammation, synaptic loss and thus rescuing cognitive deficits of these transgenic mice. We further describe that knockdown or inhibition of SMS1 decreases BACE1 stability, which is accompanied with decreased BACE1 levels in the Golgi, whereas enhanced BACE1 levels in the early endosomes and the lysosomes. The reduction of BACE1 levels induced by knockdown or inhibition of SMS1 is prevented by inhibition of lysosomes. Therefore, knockdown or inhibition of SMS1 promotes lysosomal degradation of BACE1 via modulating the intracellular trafficking of BACE1. Knockdown of SMS1 attenuates AD-like pathology through promoting lysosomal degradation of BACE1.
Subject(s)
Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor , Aspartic Acid Endopeptidases/metabolism , Lysosomes/metabolism , Presenilin-1 , Transferases (Other Substituted Phosphate Groups)/metabolism , Alzheimer Disease/genetics , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid Endopeptidases/genetics , Gene Knockdown Techniques/methods , HEK293 Cells , Humans , Lysosomes/genetics , Mice , Mice, Transgenic , Presenilin-1/genetics , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Transferases (Other Substituted Phosphate Groups)/geneticsABSTRACT
Regeneration of Pb-loaded magnetic biochar prepared with eucalypts leaf residue was studied by using EDTA-2Na as a regenerant. The desorption efficiency was found to be 84.1% in 120 min with iron leaching amount of 1.1 mg g(-1). Higher SBET and pore volume were observed in regenerated magnetic biochars and no significant band shifts occurred in FTIR spectra during 6 regeneration cycles. The decrease of Pb(II) adsorption capacity (from 52.4 to 41.5 mg g(-1)) was only found in the first regeneration cycle. Magnetic separation performance of adsorbents was not significantly affected by multiple regeneration cycles.