ß2-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function.

Down syndrome (DS) is a neurological disorder with multiple immune-related symptoms; however, crosstalk between the CNS and peripheral immune system remains unexplored. Using parabiosis and plasma infusion, we found that blood-borne factors drive synaptic deficits in DS. Proteomic analysis revealed elevation of ß2-microglobulin (B2M), a major histocompatibility complex class I (MHC-I) component, in human DS plasma. Systemic administration of B2M in wild-type mice led to synaptic and memory defects similar to those observed in DS mice. Moreover, genetic ablation of B2m or systemic administration of an anti-B2M antibody counteracts synaptic impairments in DS mice. Mechanistically, we demonstrate that B2M antagonizes NMDA receptor (NMDAR) function through interactions with the GluN1-S2 loop; blocking B2M-NMDAR interactions using competitive peptides restores NMDAR-dependent synaptic function. Our findings identify B2M as an endogenous NMDAR antagonist and reveal a pathophysiological role for circulating B2M in NMDAR dysfunction in DS and related cognitive disorders.

Apoptotic stress causes mtDNA release during senescence and drives the SASP.

Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.

Soluble SORLA Enhances Neurite Outgrowth and Regeneration through Activation of the EGF Receptor/ERK Signaling Axis.

SORLA is a transmembrane trafficking protein associated with Alzheimer's disease risk. Although SORLA is abundantly expressed in neurons, physiological roles for SORLA remain unclear. Here, we show that cultured transgenic neurons overexpressing SORLA feature longer neurites, and accelerated neurite regeneration with wounding. Enhanced release of a soluble form of SORLA (sSORLA) is observed in transgenic mouse neurons overexpressing human SORLA, while purified sSORLA promotes neurite extension and regeneration. Phosphoproteomic analyses demonstrate enrichment of phosphoproteins related to the epidermal growth factor (EGFR)/ERK pathway in SORLA transgenic mouse hippocampus from both genders. sSORLA coprecipitates with EGFR in vitro, and sSORLA treatment increases EGFR Y1173 phosphorylation, which is involved in ERK activation in cultured neurons. Furthermore, sSORLA triggers ERK activation, whereas pharmacological EGFR or ERK inhibition reverses sSORLA-dependent enhancement of neurite outgrowth. In search for downstream ERK effectors activated by sSORLA, we identified upregulation of Fos expression in hippocampus from male mice overexpressing SORLA by RNAseq analysis. We also found that Fos is upregulated and translocates to the nucleus in an ERK-dependent manner in neurons treated with sSORLA. Together, these results demonstrate that sSORLA is an EGFR-interacting protein that activates EGFR/ERK/Fos signaling to enhance neurite outgrowth and regeneration.SIGNIFICANCE STATEMENT SORLA is a transmembrane trafficking protein previously known to reduce the levels of amyloid-ß, which is critical in the pathogenesis of Alzheimer's disease. In addition, SORLA mutations are a risk factor for Alzheimer's disease. Interestingly, the SORLA ectodomain is cleaved into a soluble form, sSORLA, which has been shown to regulate cytoskeletal signaling pathways and cell motility in cells outside the nervous system. We show here that sSORLA binds and activates the EGF receptor to induce downstream signaling through the ERK serine/threonine kinase and the Fos transcription factor, thereby enhancing neurite outgrowth. These findings reveal a novel role for sSORLA in promoting neurite regeneration through the EGF receptor/ERK/Fos pathway, thereby demonstrating a potential neuroprotective mechanism involving SORLA.

SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.

UNLABELLED: Proteolytic generation of amyloidogenic amyloid ß (Aß) fragments from the amyloid precursor protein (APP) significantly contributes to Alzheimer's disease (AD). Although amyloidogenic APP proteolysis can be affected by trafficking through genetically associated AD components such as SORLA, how SORLA functionally interacts with other trafficking components is yet unclear. Here, we report that SNX27, an endosomal trafficking/recycling factor and a negative regulator of the γ-secretase complex, binds to the SORLA cytosolic tail to form a ternary complex with APP. SNX27 enhances cell surface SORLA and APP levels in human cell lines and mouse primary neurons, and depletion of SNX27 or SORLA reduces APP endosome-to-cell surface recycling kinetics. SNX27 overexpression enhances the generation of cell surface APP cleavage products such as soluble alpha-APP C-terminal fragment (CTFα) in a SORLA-dependent manner. SORLA-mediated Aß reduction is attenuated by downregulation of SNX27. This indicates that an SNX27/SORLA complex functionally interacts to limit APP distribution to amyloidogenic compartments, forming a non-amyloidogenic shunt to promote APP recycling to the cell surface. SIGNIFICANCE STATEMENT: Many genes have been identified as risk factors for Alzheimer's disease (AD), and a large proportion of these genes function to limit production or toxicity of the AD-associated amyloid ß (Aß) peptide. Whether and how these genes precisely operate to limit AD onset remains an important question. We identify binding and trafficking interactions between two of these factors, SORLA and SNX27, and demonstrate that SNX27 can direct trafficking of SORLA and the Aß precursor APP to the cell surface to limit the production of Aß. Diversion APP to the cell surface through modulation of this molecular complex may represent a complimentary strategy for future development in AD treatment.

SNX17 Mediates Dendritic Spine Maturation via p140Cap.

Sorting nexin17 (SNX17) is a member of the sorting nexin family, which plays a crucial role in endosomal trafficking. Previous research has shown that SNX17 is involved in the recycling or degradation of various proteins associated with neurodevelopmental and neurological diseases in cell models. However, the significance of SNX17 in neurological function in the mouse brain has not been thoroughly investigated. In this study, we generated Snx17 knockout mice and observed that the homozygous deletion of Snx17 (Snx17-/-) resulted in lethality. On the other hand, heterozygous mutant mice (Snx17+/-) exhibited anxiety-like behavior with a reduced preference for social novelty. Furthermore, Snx17 haploinsufficiency led to impaired synaptic transmission and reduced maturation of dendritic spines. Through GST pulldown and interactome analysis, we identified the SRC kinase inhibitor, p140Cap, as a potential downstream target of SNX17. We also demonstrated that the interaction between p140Cap and SNX17 is crucial for dendritic spine maturation. Together, this study provides the first in vivo evidence highlighting the important role of SNX17 in maintaining neuronal function, as well as regulating social novelty and anxiety-like behaviors.

P-tau217 correlates with neurodegeneration in Alzheimer's disease, and targeting p-tau217 with immunotherapy ameliorates murine tauopathy.

Neuronal loss is the central issue in Alzheimer's disease (AD), yet no treatment developed so far can halt AD-associated neurodegeneration. Here, we developed a monoclonal antibody (mAb2A7) against 217 site-phosphorylated human tau (p-tau217) and observed that p-tau217 levels positively correlated with brain atrophy and cognitive impairment in AD patients. Intranasal administration efficiently delivered mAb2A7 into male PS19 tauopathic mouse brain with target engagement and reduced tau pathology/aggregation with little effect on total soluble tau. Further, mAb2A7 treatment blocked apoptosis-associated neuronal loss and brain atrophy, reversed cognitive deficits, and improved motor function in male tauopathic mice. Proteomic analysis revealed that mAb2A7 treatment reversed alterations mainly in proteins associated with synaptic functions observed in murine tauopathy and AD brain. An antibody (13G4) targeting total tau also attenuated tau-associated pathology and neurodegeneration but impaired the motor function of male tauopathic mice. These results implicate p-tau217 as a potential therapeutic target for AD-associated neurodegeneration.

Cofilin phosphatases and regulation of actin dynamics.

Cofilin is a ubiquitous actin-binding factor required for the reorganization of actin filaments in eukaryotes. The dephosphorylation of cofilin enables its actin severing and depolymerizing activity and drives directional cell motility, thus providing a simple phosphoregulatory mechanism for actin reorganization. To date, two cofilin-specific phosphatases have been identified: Slingshot and Chronophin. These cofilin phosphatases are unrelated in sequence and regulatory properties, each potentially providing a unique mechanism for cofilin activation under varying biological circumstances.

ß2-Microglobulin coaggregates with Aß and contributes to amyloid pathology and cognitive deficits in Alzheimer's disease model mice.

Extensive studies indicate that ß-amyloid (Aß) aggregation is pivotal for Alzheimer's disease (AD) progression; however, cumulative evidence suggests that Aß itself is not sufficient to trigger AD-associated degeneration, and whether other additional pathological factors drive AD pathogenesis remains unclear. Here, we characterize pathogenic aggregates composed of ß2-microglobulin (ß2M) and Aß that trigger neurodegeneration in AD. ß2M, a component of major histocompatibility complex class I (MHC class I), is upregulated in the brains of individuals with AD and constitutes the amyloid plaque core. Elevation of ß2M aggravates amyloid pathology independent of MHC class I, and coaggregation with ß2M is essential for Aß neurotoxicity. B2m genetic ablation abrogates amyloid spreading and cognitive deficits in AD mice. Antisense oligonucleotide- or monoclonal antibody-mediated ß2M depletion mitigates AD-associated neuropathology, and inhibition of ß2M-Aß coaggregation with a ß2M-based blocking peptide ameliorates amyloid pathology and cognitive deficits in AD mice. Our findings identify ß2M as an essential factor for Aß neurotoxicity and a potential target for treating AD.

Trem2 deletion enhances tau dispersion and pathology through microglia exosomes.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aß and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer's disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive. METHODS: Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes. RESULTS: Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia. CONCLUSION: Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.

LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions.

BACKGROUND: Microglia plays crucial roles in Alzheimer's disease (AD) development. Triggering receptor expressed on myeloid cells 2 (TREM2) in association with DAP12 mediates signaling affecting microglia function. Here we study the negative regulation of TREM2 functions by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), an inhibitory receptor bearing ITIM motifs. METHODS: To specifically interrogate LILRB2-ligand (oAß and PS) interactions and microglia functions, we generated potent antagonistic LILRB2 antibodies with sub-nanomolar level activities. The biological effects of LILRB2 antagonist antibody (Ab29) were studied in human induced pluripotent stem cell (iPSC)-derived microglia (hMGLs) for migration, oAß phagocytosis, and upregulation of inflammatory cytokines. Effects of the LILRB2 antagonist antibody on microglial responses to amyloid plaques were further studied in vivo using stereotaxic grafted microglia in 5XFAD mice. RESULTS: We confirmed the expression of both LILRB2 and TREM2 in human brain microglia using immunofluorescence. Upon co-ligation of the LILRB2 and TREM2 by shared ligands oAß or PS, TREM2 signaling was significantly inhibited. We identified a monoclonal antibody (Ab29) that blocks LILRB2/ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2. Further, Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAß-lipoprotein complex in hMGL and microglia cell line HMC3. In vivo studies showed significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis when 5XFAD mice were treated with Ab29. CONCLUSIONS: This study revealed for the first time the molecular mechanisms of LILRB2-mediated inhibition of TREM2 signaling in microglia and demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. Translationally, a LILRB2 antagonist antibody completely rescued the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions.

USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aß generation.

Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted ß cleavage of APP and Aß generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

Isolation and characterization of cytoplasmic cofilin-actin rods.

Cofilin-actin bundles (rods), which form in axons and dendrites of stressed neurons, lead to synaptic dysfunction and may mediate cognitive deficits in dementias. Rods form abundantly in the cytoplasm of non-neuronal cells in response to many treatments that induce rods in neurons. Rods in cell lysates are not stable in detergents or with added calcium. Rods induced by ATP-depletion and released from cells by mechanical lysis were first isolated from two cell lines expressing chimeric actin-depolymerizing factor (ADF)/cofilin fluorescent proteins by differential and equilibrium sedimentation on OptiPrep gradients and then from neuronal and non-neuronal cells expressing only endogenous proteins. Rods contain ADF/cofilin and actin in a 1:1 ratio. Isolated rods are stable in dithiothreitol, EGTA, Ca(2+), and ATP. Cofilin-GFP-containing rods are stable in 500 mM NaCl, whereas rods formed from endogenous proteins are significantly less stable in high salt. Proteomic analysis of rods formed from endogenous proteins identified other potential components whose presence in rods was examined by immunofluorescence staining of cells. Only actin and ADF/cofilin are in rods during all phases of their formation; furthermore, the rapid assembly of rods in vitro from these purified proteins at physiological concentration shows that they are the only proteins necessary for rod formation. Cytoplasmic rod formation is inhibited by cytochalasin D and jasplakinolide. Time lapse imaging of rod formation shows abundant small needle-shaped rods that coalesce over time. Rod filament lengths measured by ultrastructural tomography ranged from 22 to 1480 nm. These results suggest rods form by assembly of cofilin-actin subunits, followed by self-association of ADF/cofilin-saturated F-actin.

RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation.

Tauopathies are a group of neurodegenerative diseases characterized by hyperphosphorylation of the microtubule-binding protein, tau, and typically feature axon impairment and synaptic dysfunction. Cyclin-dependent kinase5 (Cdk5) is a major tau kinase and its activity requires p35 or p25 regulatory subunits. P35 is subjected to rapid proteasomal degradation in its membrane-bound form and is cleaved by calpain under stress to a stable p25 form, leading to aberrant Cdk5 activation and tau hyperphosphorylation. The type Ib transmembrane protein RPS23RG1 has been implicated in Alzheimer's disease (AD). However, physiological and pathological roles for RPS23RG1 in AD and other tauopathies are largely unclear. Herein, we observed retarded axon outgrowth, elevated p35 and p25 protein levels, and increased tau phosphorylation at major Cdk5 phosphorylation sites in Rps23rg1 knockout (KO) mice. Both downregulation of p35 and the Cdk5 inhibitor roscovitine attenuated tau hyperphosphorylation and axon outgrowth impairment in Rps23rg1 KO neurons. Interestingly, interactions between the RPS23RG1 carboxyl-terminus and p35 amino-terminus promoted p35 membrane distribution and proteasomal degradation. Moreover, P301L tau transgenic (Tg) mice showed increased tau hyperphosphorylation with reduced RPS23RG1 levels and impaired axon outgrowth. Overexpression of RPS23RG1 markedly attenuated tau hyperphosphorylation and axon outgrowth defects in P301L tau Tg neurons. Our results demonstrate the involvement of RPS23RG1 in tauopathy disorders, and implicate a role for RPS23RG1 in inhibiting tau hyperphosphorylation through homeostatic p35 degradation and suppression of Cdk5 activation. Reduced RPS23RG1 levels in tauopathy trigger aberrant Cdk5-p35 activation, consequent tau hyperphosphorylation, and axon outgrowth impairment, suggesting that RPS23RG1 may be a potential therapeutic target in tauopathy disorders.

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid ß (Aß) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aß- and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aß-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.

Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and curate a comprehensive atlas comprising ATAC-seq, ChIP-seq, RNA-seq, and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates up-regulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, in which SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aß uptake in an APOE-dependent manner in vitro and attenuated Aß uptake/clearance in mouse AD brain xenotransplants. Using this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.

Cyclin-Dependent Kinase 5-Dependent BAG3 Degradation Modulates Synaptic Protein Turnover.

BACKGROUND: Synaptic protein dyshomeostasis and functional loss is an early invariant feature of Alzheimer's disease (AD), yet the unifying etiological pathway remains largely unknown. Knowing that cyclin-dependent kinase 5 (CDK5) plays critical roles in synaptic formation and degeneration, its phosphorylation targets were reexamined in search of candidates with direct global impacts on synaptic protein dynamics, and the associated regulatory network was also analyzed. METHODS: Quantitative phosphoproteomics and bioinformatics analyses were performed to identify top-ranked candidates. A series of biochemical assays was used to investigate the associated regulatory signaling networks. Histological, electrochemical, and behavioral assays were performed in conditional knockout, small hairpin RNA-mediated knockdown, and AD-related mice models to evaluate the relevance of CDK5 to synaptic homeostasis and functions. RESULTS: Among candidates with known implications in synaptic modulations, BAG3 ranked the highest. CDK5-mediated phosphorylation on S297/S291 (mouse/human) destabilized BAG3. Loss of BAG3 unleashed the selective protein degradative function of the HSP70 machinery. In neurons, this resulted in enhanced degradation of a number of glutamatergic synaptic proteins. Conditional neuronal knockout of Bag3 in vivo led to impairment of learning and memory functions. In human AD and related mouse models, aberrant CDK5-mediated loss of BAG3 yielded similar effects on synaptic homeostasis. Detrimental effects of BAG3 loss on learning and memory functions were confirmed in these mice, and such effects were reversed by ectopic BAG3 reexpression. CONCLUSIONS: Our results highlight that the neuronal CDK5-BAG3-HSP70 signaling axis plays a critical role in modulating synaptic homeostasis. Dysregulation of the signaling pathway directly contributes to synaptic dysfunction and AD pathogenesis.

Bringing Order out of Chaos: Establishing an Epistatic Relationship between CD33 and TREM2.

TREM2 and CD33 are microglial receptors associated with Alzheimer's disease (AD) risk. In this issue of Neuron, Griciuc et al. (2019) demonstrate opposing effects of CD33 and TREM2 on AD phenotypes, where CD33 deletion promotes neuroprotection in a manner dependent on TREM2.

Role of Rab GTPases in Alzheimer's Disease.

Alzheimer's disease (AD) comprises two major pathological hallmarks: extraneuronal deposition of ß-amyloid (Aß) peptides ("senile plaques") and intraneuronal aggregation of the microtubule-associated protein tau ("neurofibrillary tangles"). Aß is derived from sequential cleavage of the ß-amyloid precursor protein by ß- and γ-secretases, while aggregated tau is hyperphosphorylated in AD. Mounting evidence suggests that dysregulated trafficking of these AD-related proteins contributes to AD pathogenesis. Rab proteins are small GTPases that function as master regulators of vesicular transport and membrane trafficking. Multiple Rab GTPases have been implicated in AD-related protein trafficking, and their expression has been observed to be altered in postmortem AD brain. Here we review current implicated roles of Rab GTPase dysregulation in AD pathogenesis. Further elucidation of the pathophysiological role of Rab GTPases will likely reveal novel targets for AD therapeutics.

SNX8 Enhances Non-amyloidogenic APP Trafficking and Attenuates Aß Accumulation and Memory Deficits in an AD Mouse.

Dysregulation of various APP trafficking components in the endosome has been previously implicated in Alzheimer's disease (AD). Although single nucleotide polymorphisms within the gene locus encoding the endosomal component, SNX8 have been previously associated with AD, how SNX8 levels are altered and its contribution to AD onset is currently unknown. Here, we observe decreased expression of SNX8 in human AD and AD mouse brain. SNX8 predominantly localized to early and late endosomes, where SNX8 overexpression enhanced total APP levels, cell surface APP distribution and consequent soluble APPα cleavage. SNX8 depletion resulted in elevated ß-amyloid (Aß) levels, while SNX8 overexpression reduced Aß levels in cells and in an APP/PS1 AD mouse model. Importantly, SNX8 overexpression rescued cognitive impairment in APP/PS1 mice. Together, these results implicate a neuroprotective role for SNX8 in enhancing non-amyloidogenic APP trafficking and processing pathways. Given that endosomal dysfunction is an early event in AD, restoration of dysfunctional endosomal components such as SNX8 may be beneficial in future therapeutic strategies.