Cell-to-cell transmitted alpha-synuclein recapitulates experimental Parkinson's disease.

Parkinson's disease is characterized by a progressive accumulation of alpha-Synuclein (αSyn) neuronal inclusions called Lewy bodies in the nervous system. Lewy bodies can arise from the cell-to-cell propagation of αSyn, which can occur via sequential steps of secretion and uptake. Here, by fusing a removable short signal peptide to the N-terminus of αSyn, we developed a novel mouse model with enhanced αSyn secretion and cell-to-cell transmission. Expression of the secreted αSyn in the mouse brain was under the control of a novel hybrid promoter in combination with adeno-associated virus serotype 9 (AAV9). This combination of promoter and viral vector induced a robust expression in neurons but not in the glia of injected mice. Biochemical characterization of the secreted αSyn revealed that, in cultured cells, this protein is released to the extracellular milieu via conventional secretion. The released αSyn is then internalized and processed by acceptor cells via the endosome-lysosome pathway indicating that the secreted αSyn is cell-to-cell transmitted. The secreted αSyn is aggregation-prone and amyloidogenic, and when expressed in the brain of wild-type non-transgenic mice, it induces a Parkinson's disease-like phenotype that includes a robust αSyn pathology in the substantia nigra, neuronal loss, neuroinflammation, and motor deficits, all the key features of experimental animal models of Parkinson's disease. In summary, a novel animal model of Parkinson's disease based on enhanced cell-to-cell transmission of αSyn was developed. The neuron-produced cell-to-cell transmitted αSyn triggers all phenotypic features of experimental Parkinson's disease in mice.

A novel splicing variant of DJ-1 in Parkinson's disease induces mitochondrial dysfunction.

Several studies have identified mutations in neuroprotective genes in a few cases of Parkinson's disease (PD); however, the role of alternative splicing changes in PD remains unelucidated. Based on the transcriptome analysis of substantia nigra (SN) tissues obtained from PD cases and age-matched healthy controls, we identified a novel alternative splicing variant of DJ-1, lacking exon 6 (DJ-1 ΔE6), frequently detected in the SN of patients with PD. We found that the exon 6 skipping of DJ-1 induces mitochondrial dysfunction and impaired antioxidant capability. According to an in silico modeling study, the exon 6 skipping of DJ-1 disrupts the structural state suitable for the oxidation of the cysteine 106 residue that is a prerequisite for activating its neuroprotective roles. Our results suggest that change in DJ-1 alternative splicing may contribute to PD progression and provide an insight for studying PD etiology and its potential therapeutic targets.

CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy.

As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed the gene expression profile of microglia in a mouse model of MSA (MBP29-hα-syn) and identified a disease-associated expression profile and upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that CSF1 receptor-mediated depletion of myeloid cells using PLX5622 modifies the disease progression and neuropathological phenotype in this mouse model. Intriguingly, sex-balanced analysis of myeloid cell depletion in MBP29-hα-syn mice revealed a two-faced outcome comprising an improved survival rate accompanied by a delayed onset of neurological symptoms in contrast to severely impaired motor functions. Furthermore, PLX5622 reversed gene expression profiles related to myeloid cell activation but reduced gene expression associated with transsynaptic signaling and signal release. While transcriptional changes were accompanied by a reduction of dopaminergic neurons in the SNpc, striatal neuritic density was increased upon myeloid cell depletion in MBP29-hα-syn mice. Together, our findings provide insight into the complex, two-faced role of myeloid cells in the context of MSA emphasizing the importance to carefully balance the beneficial and adverse effects of CSF1R inhibition in different models of neurodegenerative disorders before its clinical translation.SIGNIFICANCE STATEMENT Myeloid cells have been implicated as detrimental in the disease pathogenesis of multiple system atrophy. However, long-term CSF1R-dependent depletion of these cells in a mouse model of multiple system atrophy demonstrates a two-faced effect involving an improved survival associated with a delayed onset of disease and reduced inflammation which was contrasted by severely impaired motor functions, synaptic signaling, and neuronal circuitries. Thus, this study unraveled a complex role of myeloid cells in multiple system atrophy, which indicates important functions beyond the previously described disease-associated, destructive phenotype and emphasized the need of further investigation to carefully and individually fine-tune immunologic processes in different neurodegenerative diseases.

Reconsideration of Alzheimer's Disease Therapy from a Viewpoint of Amyloidogenic Evolvability.

 Presuming that Alzheimer's disease (AD) might represent an antagonistic pleiotropic phenomenon derived from the evolvability of multiple amyloidogenic proteins, targeting such proteins simultaneously could enhance therapeutic efficacy. Furthermore, considering that amyloid-ß (Aß) immunotherapies during reproductive life stage might adversely decrease Aß evolvability in an offspring's brain, the disease-modifying Aß immunotherapies should be limited to post-reproductive time in lifespan. Thus, current Aß immunotherapy strategies should be revised accordingly. Given that the "adiponectin paradox" might underlie both amyloidosis and cognitive dysfunction in aging brain, blocking activin signaling situated downstream of the adiponectin paradox might be an alternative strategy to prevent AD.

Possible Role of Activin in the Adiponectin Paradox-Induced Progress of Alzheimer's Disease.

Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer's disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-ß (Aß) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor ß (TGFß) superfamily of peptides, to antagonistic pleiotropy effects of APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFß increases during aging. Also, activin/TGFß signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aß42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFß receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target.

Diabetes, inflammation, and the adiponectin paradox: Therapeutic targets in SARS-CoV-2.

Aging and pre-existing conditions in older patients increase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) severity and its complications, although the causes remain unclear. Apart from acute pulmonary syndrome, Coronavirus 2019 (COVID-19) can increasingly induce chronic conditions. Importantly, SARS-CoV-2 triggers de novo type 2 diabetes mellitus (T2DM) linked to age-associated cardiovascular disease (CVD), cancers, and neurodegeneration. Mechanistically, SARS-CoV-2 induces inflammation, possibly through damage-associated molecular pattern (DAMP) signaling and 'cytokine storm,' causing insulin resistance and the adiponectin (APN) paradox, a phenomenon linking metabolic dysfunction to chronic disease. Accordingly, preventing the APN paradox by suppressing APN-related inflammatory signaling might prove beneficial. A better understanding could uncover novel therapies for SARS-CoV-2 and its chronic disorders.

Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease.

Here we describe mechanistically distinct enzymes (a kinase, a guanosine triphosphatase, and a ubiquitin protein hydrolase) that function in disparate biochemical pathways and can also act in concert to mediate a series of redox reactions. Each enzyme manifests a second, noncanonical function-transnitrosylation-that triggers a pathological biochemical cascade in mouse models and in humans with Alzheimer's disease (AD). The resulting series of transnitrosylation reactions contributes to synapse loss, the major pathological correlate to cognitive decline in AD. We conclude that enzymes with distinct primary reaction mechanisms can form a completely separate network for aberrant transnitrosylation. This network operates in the postreproductive period, so natural selection against such abnormal activity may be decreased.

Connecting Alzheimer's Disease With Diabetes Mellitus Through Amyloidogenic Evolvability.

Type 2 diabetes mellitus (T2DM) has been clearlylinked to oxidative stress and amylin amyloidosis in pancreatic ß-cells. Yet despite extensive investigation, the biological significance of this is not fully understood. Recently, we proposed that Alzheimer's disease (AD)-relevant amyloidogenic proteins (APs), such as amyloid-ß (Aß) and tau, might be involved in evolvability against diverse stressors in the brain. Given the analogous cellular stress environments shared by both T2DM and AD, the objective of this study is to explore T2DM pathogenesis from the viewpoint of amyloidogenic evolvability. Similar to AD-related APs, protofibrillar amylin might confer resistance against the multiple stressors in ß-cells and be transmitted to offspring to deliver stress information, in the absence of which, type 1 DM (T1DM) in offspring might develop. On the contrary, T2DM may be manifested through an antagonistic pleiotropy mechanism during parental aging. Such evolvability-associated processes might be affected by parental diabetic conditions, including T1DM and T2DM. Furthermore, the T2DM-mediated increase in AD risk during aging might be attributed to an interaction of amylin with AD-related APs through evolvability, in which amylin protofibrillar formation presumably caused by adiponectin (APN) resistance could increase protofibril formation of AD-related APs in evolvability and subsequently lead to T2DM promotion of AD through antagonistic pleiotropy in aging. This suggests that targeting APN combined with an anti-T2DM agent might be therapeutic against neurodegeneration. Collectively, T1DM and T2DM might be linked through amylin evolvability, and a better understanding of amyloidogenic evolvability might also reveal clues to therapeutic interventions for AD comorbid with T2DM.

LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies.

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein-mediated microglial neurotoxicity via lowering of tumor necrosis factor-α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

Non-toxic HSC Transplantation-Based Macrophage/Microglia-Mediated GDNF Delivery for Parkinson's Disease.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body-like pathology.

Parkinson's disease (PD) is a neurological disorder characterized by the progressive accumulation of neuronal α-synuclein (αSyn) inclusions called Lewy bodies. It is believed that Lewy bodies spread throughout the nervous system due to the cell-to-cell propagation of αSyn via cycles of secretion and uptake. Here, we investigated the internalization and intracellular accumulation of exogenous αSyn, two key steps of Lewy body pathogenesis, amplification and spreading. We found that stable αSyn fibrils substantially accumulate in different cell lines upon internalization, whereas αSyn monomers, oligomers, and dissociable fibrils do not. Our data indicate that the uptake-mediated accumulation of αSyn in a human-derived neuroblastoma cell line triggered an adaptive response that involved proteins linked to ubiquitin ligases of the S-phase kinase-associated protein 1 (SKP1), cullin-1 (Cul1), and F-box domain-containing protein (SCF) family. We found that SKP1, Cul1, and the F-box/LRR repeat protein 5 (FBXL5) colocalized and physically interacted with internalized αSyn in cultured cells. Moreover, the SCF containing the F-box protein FBXL5 (SCFFBXL5) catalyzed αSyn ubiquitination in reconstitution experiments in vitro using recombinant proteins and in cultured cells. In the human brain, SKP1 and Cul1 were recruited into Lewy bodies from brainstem and neocortex of patients with PD and related neurological disorders. In both transgenic and nontransgenic mice, intracerebral administration of exogenous αSyn fibrils triggered a Lewy body-like pathology, which was amplified by SKP1 or FBXL5 loss of function. Our data thus indicate that SCFFXBL5 regulates αSyn in vivo and that SCF ligases may constitute targets for the treatment of PD and other α-synucleinopathies.

NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model.

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/- mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/- phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/- mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC.

HIV and Alzheimer's disease: complex interactions of HIV-Tat with amyloid ß peptide and Tau protein.

In patients infected with the human immunodeficiency virus (HIV), the HIV-Tat protein may be continually produced despite adequate antiretroviral therapy. As the HIV-infected population is aging, it is becoming increasingly important to understand how HIV-Tat may interact with proteins such as amyloid ß and Tau which accumulate in the aging brain and eventually result in Alzheimer's disease. In this review, we examine the in vivo data from HIV-infected patients and animal models and the in vitro experiments that show how protein complexes between HIV-Tat and amyloid ß occur through novel protein-protein interactions and how HIV-Tat may influence the pathways for amyloid ß production, degradation, phagocytosis, and transport. HIV-Tat may also induce Tau phosphorylation through a cascade of cellular processes that lead to the formation of neurofibrillary tangles, another hallmark of Alzheimer's disease. We also identify gaps in knowledge and future directions for research. Available evidence suggests that HIV-Tat may accelerate Alzheimer-like pathology in patients with HIV infection which cannot be impacted by current antiretroviral therapy.

Pathogenesis of age-related HIV neurodegeneration.

People over the age of 50 are the fastest growing segment of the HIV-infected population in the USA. Although antiretroviral therapy has remarkable success controlling the systemic HIV infection, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group, and cognitive deficits appear more severe in aged patients with HIV. The mechanisms of HAND in the aged population are not completely understood; a leading hypothesis is that aged individuals with HIV might be at higher risk of developing Alzheimer's disease (AD) or one of the AD-related dementias (ADRD). There are a number of mechanisms through which chronic HIV disease alone or in combination with antiretroviral therapy and other comorbidities (e.g., drug use, hepatitis C virus (HCV)) might be contributing to HAND in individuals over the age of 50 years, including (1) overlapping pathogenic mechanisms between HIV and aging (e.g., decreased proteostasis, DNA damage, chronic inflammation, epigenetics, vascular), which could lead to accelerated cellular aging and neurodegeneration and/or (2) by promoting pathways involved in AD/ADRD neuropathogenesis (e.g., triggering amyloid ß, Tau, or α-synuclein accumulation). In this manuscript, we will review some of the potential common mechanisms involved and evidence in favor and against a role of AD/ADRD in HAND.

The Amazon rain forest plant Uncaria tomentosa (cat's claw) and its specific proanthocyanidin constituents are potent inhibitors and reducers of both brain plaques and tangles.

Brain aging and Alzheimer's disease both demonstrate the accumulation of beta-amyloid protein containing "plaques" and tau protein containing "tangles" that contribute to accelerated memory loss and cognitive decline. In the present investigation we identified a specific plant extract and its constituents as a potential alternative natural solution for preventing and reducing both brain "plaques and tangles". PTI-00703 cat's claw (Uncaria tomentosa from a specific Peruvian source), a specific and natural plant extract from the Amazon rain forest, was identified as a potent inhibitor and reducer of both beta-amyloid fibrils (the main component of "plaques") and tau protein paired helical filaments/fibrils (the main component of "tangles"). PTI-00703 cat's claw demonstrated both the ability to prevent formation/aggregation and disaggregate preformed Aß fibrils (1-42 and 1-40) and tau protein tangles/filaments. The disaggregation/dissolution of Aß fibrils occurred nearly instantly when PTI-00703 cat's claw and Aß fibrils were mixed together as shown by a variety of methods including Thioflavin T fluorometry, Congo red staining, Thioflavin S fluorescence and electron microscopy. Sophisticated structural elucidation studies identified the major fractions and specific constituents within PTI-00703 cat's claw responsible for both the observed "plaque" and "tangle" inhibitory and reducing activity. Specific proanthocyanidins (i.e. epicatechin dimers and variants thereof) are newly identified polyphenolic components within Uncaria tomentosa that possess both "plaque and tangle" reducing and inhibitory activity. One major identified specific polyphenol within PTI-00703 cat's claw was epicatechin-4ß-8-epicatechin (i.e. an epicatechin dimer known as proanthocyanidin B2) that markedly reduced brain plaque load and improved short-term memory in younger and older APP "plaque-producing" (TASD-41) transgenic mice (bearing London and Swedish mutations). Proanthocyanidin B2 was also a potent inhibitor of brain inflammation as shown by reduction in astrocytosis and gliosis in TASD-41 transgenic mice. Blood-brain-barrier studies in Sprague-Dawley rats and CD-1 mice indicated that the major components of PTI-00703 cat's claw crossed the blood-brain-barrier and entered the brain parenchyma within 2 minutes of being in the blood. The discovery of a natural plant extract from the Amazon rain forest plant (i.e. Uncaria tomentosa or cat's claw) as both a potent "plaque and tangle" inhibitor and disaggregator is postulated to represent a potential breakthrough for the natural treatment of both normal brain aging and Alzheimer's disease.

A comprehensive screening of copy number variability in dementia with Lewy bodies.

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

Possible Role of the Polyglutamine Elongation in Evolution of Amyloid-Related Evolvability.

The polyglutamine (polyQ) diseases, such as Huntington's disease and the spinocerebellar ataxias, are characterized by the accumulation of elongated polyQ sequences (epolyQ) and mostly occur during midlife. Considering that polyQ disorders have not been selected out in evolution, there might be important physiological functions of epolyQ during development and/or reproduction. In a similar context, the physiological functions of neurodegeneration-associated amyloidogenic proteins (APs), such as ß-amyloid in Alzheimer's disease and α-synuclein in Parkinson's disease, remain elusive. In this regard, we recently proposed that evolvability for coping with diverse stressors in the brain, which is beneficial for offspring, might be relevant to the physiological functions of APs. Given analogous properties of APs and epolyQ in terms of neurotoxic amyloid-fibril formation, the objective of this paper is to determine whether evolvability could also be applied to the physiological functions of epolyQ. Indeed, APs and epolyQ are similar in many ways, including functional redundancy of non-amyloidogenic homologues, hormesis conferred by the heterogeneity of the stress-induced protein aggregates, the transgenerational prion-like transmission of the protein aggregates via germ cells, and the antagonistic pleiotropy relationship between evolvability and neurodegenerative disease. Given that epolyQ is widely expressed from microorganisms to human brain, whereas APs are only identified in vertebrates, evolvability of epolyQ is considered to be much more primitive compared to those of APs during evolution. Collectively, epolyQ may be not only be important in the pathophysiology of polyQ diseases, but also in the evolution of amyloid-related evolvability.

T-complex protein 1-ring complex enhances retrograde axonal transport by modulating tau phosphorylation.

The cytosolic chaperonin T-complex protein (TCP) 1-ring complex (TRiC) has been shown to exert neuroprotective effects on axonal transport through clearance of mutant Huntingtin (mHTT) in Huntington's disease. However, it is presently unknown if TRiC also has any effect on axonal transport in wild-type neurons. Here, we examined how TRiC impacted the retrograde axonal transport of brain-derived neurotrophic factor (BDNF). We found that expression of a single TRiC subunit significantly enhanced axonal transport of BDNF, leading to an increase in instantaneous velocity with a concomitant decrease in pauses for retrograde BDNF transport. The transport enhancing effect by TRiC was dependent on endogenous tau expression because no effect was seen in neurons from tau knockout mice. We showed that TRiC regulated the level of cyclin-dependent kinase 5 (CDK5)/p35 positively, contributing to TRiC-mediated tau phosphorylation (ptau). Expression of a single TRiC subunit increased the level of ptau while downregulation of the TRiC complex decreased ptau. We further demonstrated that TRiC-mediated increase in ptau induced detachment of tau from microtubules. Our study has thus revealed that TRiC-mediated increase in tau phosphorylation impacts retrograde axonal transport.

Alterations in brain TREM2 and Amyloid-ß levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-ß, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aß protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aß levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aß in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aß and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.