• Aging
• Alzheimer´s disease. ‘
• Cholesterol
• Cholinergic signaling
• Membrane heterogeneity
• Membrane lipids
• Nicotinic acetylcholine receptor

• Alzheimer’s disease
• Intracellular amyloid β
• Membrane raft
• Sphingomyelin synthase
• Synaptic plasticity

• Animals
• Transferases (Other Substituted Phosphate Groups)/genetics
• Transferases (Other Substituted Phosphate Groups)/metabolism
• Alzheimer Disease/genetics
• Alzheimer Disease/metabolism
• Disease Models, Animal
• Cognitive Dysfunction/metabolism
• Cognitive Dysfunction/genetics
• Mice
• Mice, Transgenic
• Mice, Knockout
• Amyloid beta-Peptides/metabolism
• Male
• Maze Learning/physiology
• Hippocampus/metabolism
• Mice, Inbred C57BL

• APP intercellular domain
• Alzheimer‘s disease
• Amyloid precursor protein processing
• Aβ generation
• Gal3st1/CST7)
• Lipid homeostasis
• Lipid rafts
• Sulfatide
• β-secretase
• γ-secretase

• Mice
• Animals
• Humans
• Alzheimer Disease/metabolism
• Amyloid Precursor Protein Secretases/metabolism
• Sulfoglycosphingolipids
• Amyloid beta-Peptides/metabolism
• Aspartic Acid Endopeptidases/metabolism
• Amyloid beta-Protein Precursor/genetics
• Amyloid beta-Protein Precursor/metabolism
• Mice, Transgenic

• Alzheimer's disease
• conformation
• ganglioside GM1
• presenilin1
• β-amyloid protein

• Humans
• Alzheimer Disease/metabolism
• Amyloid beta-Protein Precursor
• Amyloid Precursor Protein Secretases/metabolism
• Amyloid Precursor Protein Secretases/therapeutic use
• G(M1) Ganglioside
• Cryoelectron Microscopy

• 2022ZD0211800 STI2030-Major Projects
• 2021B-01-01 Changping laboratory
• 2020YFA0509300 National Key Research and Development Program of China
• Ministry of Science and Technology of China
• 81920108015 National Natural Science Foundation of China
• 2020C04001 Key R&D Program of Zhejiang Province
• National Key Research and Development Program of China
• National Natural Science Foundation of China

• Biological sciences
• Molecular biology
• Molecular interaction

• R21 AI178391 NIAID NIH HHS

• CD36
• Fibrosis
• Lipid rafts
• Notch1
• γ-Secretase

• Animals
• Mice
• Amyloid Precursor Protein Secretases/antagonists & inhibitors
• CD36 Antigens/deficiency
• CD36 Antigens/genetics
• CD36 Antigens/metabolism
• Diet/adverse effects
• Gene Deletion
• Hep G2 Cells
• Hepatocytes/metabolism
• Liver Cirrhosis/etiology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/prevention & control
• Membrane Microdomains
• Non-alcoholic Fatty Liver Disease/etiology
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/prevention & control
• Peptide Fragments/antagonists & inhibitors
• Peptide Fragments/chemistry
• Peptide Fragments/metabolism
• Phenotype
• Receptor, Notch1/chemistry
• Receptor, Notch1/metabolism
• Signal Transduction
• Humans

• Amyloid beta
• Amyloid precursor protein
• Beta secretase
• Early endosomes
• Gamma secretase
• Neurons
• Proximity ligation assay

• Humans
• Amyloid beta-Protein Precursor
• Amyloid beta-Peptides
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Induced Pluripotent Stem Cells
• Alzheimer Disease
• Neurons

• 681712 European Research Council
• University of Gothenburg
• Demensfonden
• Åhlén-stiftelsen
• Gun och Bertil Stohnes Stiftelse
• Magnus Bergvalls Stiftelse
• Alzheimerfonden
• Stiftelsen för Gamla Tjänarinnor
• Vetenskapsrådet
• Swedish State Support for Clinical Research

• Alzheimer's disease
• ER-mitochondria contacts
• MCU
• Mitochondrial calcium signaling
• NCLX
• Presenilin

• Amyloid Precursor Protein Secretases/genetics
• Ligands

• U01 CA244109 NCI NIH HHS
• R01 AG008200 NIA NIH HHS
• R21 AG072232 NIA NIH HHS
• R01 GM126542 NIGMS NIH HHS
• R35 GM134948 NIGMS NIH HHS
• R01 NS047229 NINDS NIH HHS
• R00 CA226366 NCI NIH HHS
• R01 GM112081 NIGMS NIH HHS

• Alzheimer’s disease
• cognition-oriented treatment
• communication
• interdisciplinary approaches
• multidomain intervention
• multimodal intervention
• nutritional approaches
• oral health
• physical activity
• socioeconomic factors

Mutations of the NOTCH1 gene are a validated prognostic marker in chronic lymphocytic leukemia and a potential predictive marker for anti-CD20-based therapies. At present, the most frequent pathological alteration of the NOTCH1 gene is due to somatic genetic mutations, which have a multifaceted functional impact. However, beside NOTCH1 mutations, other factors may lead to activation of the NOTCH1 pathway, and these include mutations of FBXW7, MED12, SPEN, SF3B1 as well as other B-cell pathways. Understanding the preferential strategies though which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

• FBXW7
• NOTCH1
• chronic lymphocytic leukemia
• gene mutations

Like protein phosphorylation, O-GlcNAcylation is a common post-translational protein modification. We already reported that O-GlcNAcylation of amyloid precursor protein (APP) in response to insulin signaling reduces neurotoxic amyloid-β (Aβ) production via inhibition of APP endocytosis. Internalized APP is delivered to endosomes and lysosomes where Aβ is produced. However, the molecular mechanism involved in the effect of APP O-GlcNAcylation on APP trafficking remains unknown. To investigate the relationship between APP O-GlcNAcylation and APP endocytosis, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing APP and BACE1, and cultured rat hippocampal neurons. The present study showed that APP O-GlcNAcylation translocated APP from lipid raft to non-raft microdomains in the plasma membrane by using immunocytochemistry and discontinuous sucrose gradients method. By using the biotinylation method, we also found that APP preferentially underwent endocytosis from lipid rafts and that the amount of internalized APP from lipid rafts was specifically reduced by O-GlcNAcylation. These results indicate that O-GlcNAcylation can regulate lipid raft-dependent APP endocytosis via translocation of APP into non-raft microdomains. Our findings showed a new functional role of O-GlcNAcylation for the regulation of APP trafficking, offering new mechanistic insight for Aβ production.

• Alzheimer’s disease
• O-GlcNAcylation
• amyloid precursor protein
• endocytosis
• insulin
• lipid raft

• Atherosclerosis
• Autoimmunity
• Intramembrane proteolysis
• SPPL proteases
• Signal peptide peptidase
• Spermatogenesis
• γ-Secretase

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

• Drosophila
• Notch signaling
• intracellular trafficking
• ligand-independent
• mammals
• therapeutic targeting

• Animals
• Endosomes/metabolism
• Humans
• Ligands
• Molecular Targeted Therapy
• Protein Transport
• Receptors, Notch/metabolism
• Signal Transduction

• PARP inhibitors
• PI3kb/mTOR inhibitors
• histone deacetylase inhibitors
• immunotherapy
• novel therapeutic strategies
• targeted therapies

Axonal generation of Alzheimer’s disease (AD)-associated amyloid-β (Aβ) plays a key role in AD neuropathology, but the cellular mechanisms involved in its release have remained elusive. We previously reported that palmitoylated APP (palAPP) partitions to lipid rafts where it serves as a preferred substrate for β-secretase. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are cholesterol-rich lipid rafts that are upregulated in AD. Here, we show that downregulating MAM assembly by either RNA silencing or pharmacological modulation of the MAM-resident sigma1 receptor (S1R) leads to attenuated β-secretase cleavage of palAPP. Upregulation of MAMs promotes trafficking of palAPP to the cell surface, β-secretase cleavage, and Aβ generation. We develop a microfluidic device and use it to show that MAM levels alter Aβ generation specifically in neuronal processes and axons, but not in cell bodies. These data suggest therapeutic strategies for reducing axonal release of Aβ and attenuating β-amyloid pathology in AD.

Bhattacharyya et al. show that the modulation of mitochondrial-associated endoplasmic reticulum membranes (MAMs) via sigma-1 receptor regulates Aβ generation from axons via cell surface trafficking and β-secretase cleavage of MAM-resident palmitoylated APP (palAPP).

• AD
• APP
• Alzheimer's disease
• MAMs
• axonal Abeta
• lipid rafts
• mitochondria-associated ER membranes
• palmitoylation

• Alzheimer’s disease
• amyloid precursor protein
• confocal microscopy
• gamma secretase
• lipid raft
• membrane bilayer

The plasma membrane consists of a variety of discrete domains differing from the surrounding membrane in composition and properties. Selective partitioning of protein to these microdomains is essential for membrane functioning and integrity. Studying the nanoscale size and dynamic nature of the membrane microdomains requires advanced imaging approaches with a high spatiotemporal resolution and, consequently, expensive and specialized equipment, unavailable for most researchers and unsuited for large-scale studies. Thus, understanding of protein partitioning to the membrane microdomains in health and disease is still hampered by the lack of inexpensive live-cell approaches with an appropriate spatial resolution. Here, we have developed a novel approach based on Gaussia princeps luciferase protein-fragment complementation assay to quantitively investigate protein partitioning to cholesterol and sphingomyelin-rich domains, sometimes called ‘lipid rafts’, in intact living cells with a high-spatial resolution. In the assay, the reporter construct, carrying one half of the luciferase protein, is targeted to lipid microdomains through the fused acetylation motif from Src-family kinase Fyn. A protein of interest carries the second half of the luciferase protein. Together, this serves as a reversible real-time sensor of raft recruitment for the studied protein. We demonstrated that the assay can efficiently detect the dynamic alterations in raft localization of two disease-associated proteins: Akt and APP. Importantly, this method can be used in high-throughput screenings and other large-scale studies in living cells. This inexpensive, and easy to implement raft localization assay will benefit all researchers interested in protein partitioning in rafts.

• high-throughput screening
• lipid microdomains
• lipid rafts
• protein-fragment complementation assay

• AIBP
• Angiogenesis and hematopoiesis
• Atherogenesis
• Cholesterol efflux
• SREBP2-regulated Notch
• TLR4 signaling

The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer’s disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.

• Alzheimer’s disease
• TMEM97
• cancer
• cholesterol homeostasis
• sigma-2 receptor

• APP 99-aa long C-terminal fragment (C99)
• Alzheimer disease (AD)
• Lipid homeostasis
• Mitochondria
• Mitochondria-associated ER membranes (MAM)

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Biological Transport/physiology
• Cholesterol/metabolism
• Endoplasmic Reticulum/metabolism
• Endoplasmic Reticulum/pathology
• Humans
• Mitochondria/metabolism
• Mitochondria/pathology
• Peptide Fragments/metabolism

• R01 AG056387 NIA NIH HHS

• APP C-terminal fragment
• APP processing
• Alzheimer disease mouse model
• G-protein signaling
• adenylate cyclase
• amyloid precursor protein
• amyloidosis
• cognitive function
• lipid raft

• Amyloid Precursor Protein Secretases
• Amyloid beta-Protein Precursor
• Lipid Bilayers
• Membrane Lipids
• Membrane Microdomains

• U54 CA137788 NCI NIH HHS
• R01 NS096275 NINDS NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 AG061350 NIA NIH HHS
• U54 CA132378 NCI NIH HHS
• S06 GM008168 NIGMS NIH HHS
• RF1 AG057593 NIA NIH HHS

• Acetylgalactosamine/chemistry
• Entamoeba histolytica/genetics
• Entamoeba histolytica/metabolism
• Galactose/chemistry
• Gene Expression Regulation/drug effects
• Host-Parasite Interactions
• Isocoumarins/chemistry
• Isocoumarins/metabolism
• Isocoumarins/pharmacology
• Lectins/chemistry
• Lectins/metabolism
• Membrane Microdomains/metabolism
• Peptide Hydrolases/chemistry
• Peptide Hydrolases/genetics
• Peptide Hydrolases/metabolism
• Protein Multimerization
• Protein Subunits/chemistry
• Protein Subunits/metabolism
• Protozoan Proteins/antagonists & inhibitors
• Protozoan Proteins/genetics
• Protozoan Proteins/metabolism
• RNA Interference

• P20 GM109094 NIGMS NIH HHS
• National Institute of General Medical Sciences

Biological membranes show lateral and transverse asymmetric lipid distribution. Cholesterol (Chol) localizes in both hemilayers, but in the external one it is mostly condensed in lipid-ordered microdomains (raft domains), together with saturated phosphatidyl lipids and sphingolipids (including sphingomyelin and glycosphingolipids). Membrane asymmetries induce special membrane biophysical properties and behave as signals for several physiological and/or pathological processes. Alzheimer’s disease (AD) is associated with a perturbation in different membrane properties. Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein together with neuroinflammation and neurodegeneration are the most characteristic cellular changes observed in this disease. The extracellular presence of Aβ peptides forming senile plaques, together with soluble oligomeric species of Aβ, are considered the major cause of the synaptic dysfunction of AD. The association between Aβ peptide and membrane lipids has been extensively studied. It has been postulated that Chol content and Chol distribution condition Aβ production and posterior accumulation in membranes and, hence, cell dysfunction. Several lines of evidence suggest that Aβ partitions in the cell membrane accumulate mostly in raft domains, the site where the cleavage of the precursor AβPP by β- and γ- secretase is also thought to occur. The main consequence of the pathogenesis of AD is the disruption of the cholinergic pathways in the cerebral cortex and in the basal forebrain. In parallel, the nicotinic acetylcholine receptor has been extensively linked to membrane properties. Since its transmembrane domain exhibits extensive contacts with the surrounding lipids, the acetylcholine receptor function is conditioned by its lipid microenvironment. The nicotinic acetylcholine receptor is present in high-density clusters in the cell membrane where it localizes mainly in lipid-ordered domains. Perturbations of sphingomyelin or cholesterol composition alter acetylcholine receptor location. Therefore, Aβ processing, Aβ partitioning, and acetylcholine receptor location and function can be manipulated by changes in membrane lipid biophysics. Understanding these mechanisms should provide insights into new therapeutic strategies for prevention and/or treatment of AD. Here, we discuss the implications of lipid-protein interactions at the cell membrane level in AD.

• Alzheimer’s disease
• Aβ peptide
• acetylcholinesterase
• cell membranes
• cholesterol
• lipid rafts
• nicotinic acetylcholine receptor

Alzheimer's disease (AD) is a kind of chronic degenerative disease of the central nervous system, characteristics of cognitive dysfunction, and behavioral disability. The pathological changes include the formation of senile plaques-containing beta-amyloid (Aβ), neurofibrillary tangles (NFTs), loss of neurons, and synapses. So far, the pathogenesis of AD is still unclear. This study was aimed to review the major pathogenesis of AD-related to the published AD studies in recent 20 years.

The author retrieved information from the PubMed database up to January 2018, using various search terms and their combinations, including AD, Aβ, NFTs, pathogenesis, and genetic mutation.

The author included data from peer-reviewed journals printed in English and Chinese on pathophysiological factors in AD. He organized these informations to explain the possible pathogenesis in AD.

There are many amounts of data supporting the view that AD pathogenesis so far there mainly are Aβ toxicity, tau protein, gene mutation, synaptic damages, intermediate neurons and network abnormalities, changes in mitochondrial function, chemokines, etc., Its nosogenesis may be involved in multiple theories and involved in multiple molecular signaling pathways, including Aβ, tau protein, and synaptic anomaly; mutual relationship between the mechanisms urge jointly neuronal degeneration.

This review highlights the research advances in the pathogenesis of AD. Future research has needed to fully disclose the association between multiple pathogenesis at the same time to interdict multiple signaling pathways, etc.

• Alzheimer's Disease
• Beta-Amyloid
• Neurofibrillary Tangles
• Pathogenesis

• Alzheimer’s disease
• amyloid β
• microRNA
• pathology
• tau phosphorylation

• Alzheimer’s disease
• AβPP
• LDL receptor
• Notch
• cancer
• cell migration
• β-secretase
• γ-secretase

• Alzheimer’s disease
• TAT-tCNTF
• amyloid beta-protein
• blood-brain barrier
• hippocampal neurons

• APP proteolysis
• Membrane fluidity
• Membrane permeabilization
• Receptor mediated uptake of beta amyloid

MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer’s disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD.

• Alzheimer’s disease
• BACE1 inhibitors
• miRNAs
• γ-secretase inhibitors

• ABCA1
• amyloid precursor protein
• amyloid-β
• cholesterol
• genetics
• macrophage
• microglia
• neurons
• phagocytosis
• phospholipids

• R21 AG054890 NIA NIH HHS

• Amyloid precursor protein (APP)
• Cholesterol
• Molecular dynamics (MD)
• Synaptic plasma membrane
• γ-secretase

• 5XFAD
• PDAPP
• axonal transport
• dystrophic neurite
• neurodegeneration

• Amyloid Precursor Protein Secretases/metabolism
• Animals
• Humans
• Membrane Proteins/metabolism
• Models, Molecular
• Proteolysis
• Substrate Specificity

• Alzheimer’s disease
• Endosomal-lysosomal system
• Insulin-like growth factor II receptor
• Mannose 6-phosphate receptor
• Neurodegenerative diseases

• Alzheimer Disease/metabolism
• Alzheimer Disease/pathology
• Animals
• Cations/metabolism
• Humans
• Insulin-Like Growth Factor II/metabolism
• Lysosomes/metabolism
• Neurodegenerative Diseases/metabolism
• Receptor, IGF Type 2/chemistry
• Receptor, IGF Type 2/metabolism

• R01 AG019070 NIA NIH HHS
• R01 CA091885 NCI NIH HHS
• MOP-84480 CIHR

• Biomimetic Materials/chemistry
• Lipids/chemistry
• Membrane Proteins/chemistry
• Microscopy, Confocal
• Microspheres
• Peptides/chemistry

• U54 CA137788 NCI NIH HHS
• R01 AG026660 NIA NIH HHS
• R01 NS096275 NINDS NIH HHS
• R01 NS076117 NINDS NIH HHS
• P30 CA008748 NCI NIH HHS
• U54 CA132378 NCI NIH HHS
• S06 GM008168 NIGMS NIH HHS

• AIBP
• Notch signaling
• angiogenesis
• cholesterol
• cholesterol efflux
• lipid rafts
• lipids and lipoprotein metabolism

• Amyloid Precursor Protein Secretases/physiology
• Animals
• Carrier Proteins/biosynthesis
• Hindlimb/blood supply
• Hindlimb/metabolism
• Hindlimb/pathology
• Humans
• Ischemia/metabolism
• Ischemia/pathology
• Mice
• Mice, Knockout
• Neovascularization, Physiologic/physiology
• Phosphoproteins/biosynthesis
• Racemases and Epimerases
• Receptors, Notch/biosynthesis
• Retina/metabolism
• Retina/pathology
• Signal Transduction/physiology
• Up-Regulation/physiology
• Zebrafish

• R35 HL135737 NHLBI NIH HHS
• U01 HL100397 NHLBI NIH HHS
• R01 EY022901 NEI NIH HHS
• K99 HL114734 NHLBI NIH HHS
• R00 HL114734 NHLBI NIH HHS
• R01 HL129767 NHLBI NIH HHS
• R01 HL132155 NHLBI NIH HHS

The mechanisms behind Aβ-peptide accumulation in non-familial Alzheimer’s disease (AD) remain elusive. Proteins of the tetraspanin family modulate Aβ production by interacting to γ-secretase.

We searched for tetraspanins with altered expression in AD brains. The function of the selected tetraspanin was studied in vitro and the physiological relevance of our findings was confirmed in vivo.

Tetraspanin-6 (TSPAN6) is increased in AD brains and overexpression in cells exerts paradoxical effects on Amyloid Precursor Protein (APP) metabolism, increasing APP-C-terminal fragments (APP-CTF) and Aβ levels at the same time. TSPAN6 affects autophagosome-lysosomal fusion slowing down the degradation of APP-CTF. TSPAN6 recruits also the cytosolic, exosome-forming adaptor syntenin which increases secretion of exosomes that contain APP-CTF.

TSPAN6 is a key player in the bifurcation between lysosomal-dependent degradation and exosome mediated secretion of APP-CTF. This corroborates the central role of the autophagosomal/lysosomal pathway in APP metabolism and shows that TSPAN6 is a crucial player in APP-CTF turnover.

The online version of this article (doi:10.1186/s13024-017-0165-0) contains supplementary material, which is available to authorized users.

• Alzheimer’s disease
• Amyloid precursor protein
• Intraluminal vesicles
• Multivesicular bodies
• Tetraspanin-6

• Alzheimer
• Hippocampus
• Human brain
• Microglia
• Pathology

• Amyloid Precursor Protein Secretases/genetics
• Amyloid Precursor Protein Secretases/metabolism
• Amyloid beta-Protein Precursor/genetics
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Aspartic Acid Endopeptidases/genetics
• Aspartic Acid Endopeptidases/metabolism
• CHO Cells
• Cell Line, Transformed
• Cell Membrane/genetics
• Cell Membrane/metabolism
• Cricetinae
• Cricetulus
• Humans
• Lipoylation
• Protein Domains
• Protein Multimerization

• R01 NS045860 NINDS NIH HHS
• National Institute of Neurological Disorders and Stroke

• Aging
• Cholesterol
• Memory
• Plant sterol diet
• Presenilin1
• SAMP8