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Activation of microglia by classical inflammatory mediators can convert astrocytes into a neurotoxic A1 phenotype in a variety of neurological diseases 1 , 2 . Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease-modifying therapies. Glucagon-like peptide-1 receptor (GLP1R) agonists have been indicated as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease and Parkinson’s disease 3 – 13 . The mechanisms by which GLP1R agonists are neuroprotective are not known. Here we show that a potent, brain-penetrant long-acting GLP1R agonist, NLY01, protects against the loss of dopaminergic neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) mouse model of sporadic Parkinson’s disease 14 , 15 . NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic mouse model of α-synucleinopathy-induced neurodegeneration 16 . We found that NLY01 is a potent GLP1R agonist with favorable properties that is neuroprotective through the direct prevention of microglial-mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of its favorable properties, NLY01 should be evaluated in the treatment of Parkinson’s disease and related neurologic disorders characterized by microglial activation. Agonism of microglial glucagon-like peptide-1 receptor (GLP1R) using a brain-penetrant peptide prevents the generation of neurotoxic astrocytes and ameliorates disease progression in two rodent models of Parkinson’s disease.

Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity. Changes in autophagy have been shown to modulate lifespan in lower organisms. Here, Pyo et al. show that mice globally overexpressing the autophagy protein Atg5 live longer and are leaner than normal mice, providing the first evidence that increased autophagy extends lifespan in mammals.

Alzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R + microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

Background Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin. Method We used GBA +/L444P mice, α-synuclein knockout (SNCA −/− ) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA +/L444P mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility. Results L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA +/L444P mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA +/L444P mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA +/L444P mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA +/L444P mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA +/L444P mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA +/L444P mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA +/L444P α-synuclein (SNCA) −/− mice was nearly equal to that in SNCA −/− mice after MPTP treatment. Conclusion Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.

BACKGROUNDMicroglia-mediated brain immune changes play a role in the pathogenesis of Parkinson's disease (PD), but imaging microglia in living people with PD has relied on positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. We aimed to develop imaging of colony stimulating factor 1 receptor (CSF1R) as a microglial-sensitive marker of innate immunity.METHODSIHC using a CSF1R antibody evaluated colocalization with Iba-1 in PD (n = 4) and control (n = 4) human brain samples. Autoradiography using a CSF1R tritiated ligand in human brain samples from individuals with PD (n = 5) and in a control group (n = 4) was performed to obtain Bmax. PET imaging using a CSF1R radioligand was performed in 10 controls and 12 people with PD, and VT was compared between groups and correlated with disease severity.RESULTSIHC of CSF1R in human brain samples shows colocalization with Iba-1 and is significantly increased in brain samples from individuals with PD compared with individuals in a control group. Autoradiography revealed significantly increased CSF1R ligand binding in the inferior parietal cortex of patients with PD. [11C]CPPC PET showed higher binding in people with moderate PD compared with people in a control group and ligand binding correlated with more severe motor disability and poorer verbal fluency.CONCLUSIONThis study underscores the significance of CSF1R imaging as a promising biomarker for brain immune function in Parkinson's disease, which may be associated with cognitive and motor disease severity.FUNDINGPET imaging: the Michael J. Fox Foundation and the RMS Family Foundation. Radiotracer development: NIH (R01AG066464 and P41 EB024495). Postmortem brain tissues: NIH P30 AG066507 and BIOCARD study NIH U19 AG033655.

Although brain alterations have been reported in post-acute sequelae of SARS-CoV-2 (PASC), their prevalence and relationship to neurodegeneration remain unclear. We analyzed blood proteins and brain MRI from individuals approximately one year after mild COVID-19, categorized as Cog-PASC (with cognitive impairment), Other-PASC (without cognitive impairment), or non-PASC controls, across exploration, covariate-matched, and independent validation cohorts. In the exploration cohort, Cog-PASC showed elevated astroglial damage–associated proteins and structural and microstructural alterations across multiple cortical and subcortical regions, including cortical thinning in the cingulate and insular cortices, increased paramagnetic susceptibility in the hippocampus, and enlarged choroid plexus volume. In the age-, sex-, and education–matched cohort, cortical thinning and increased susceptibility in the cingulate remained significant. Blood proteomics revealed broader alterations involving oxidative stress responses and synaptic function in Cog-PASC, linked to neurodegenerative pathways. In the validation cohort, increased neuronal and astroglial damage-associated proteins, cortical thinning in the cingulate and insular cortices, and increased hippocampal susceptibility were demonstrated, along with enlarged choroid plexus, confirming the reproducibility of these neurodegeneration-associated alterations. These findings suggest distinct neurodegenerative processes in Cog-PASC not observed in other-PASC subtypes, even after mild COVID-19 infection. Post-acute sequelae of SARS-CoV-2 (PASC) have been linked to brain alterations, but association with cognitive problems are not well understood. Here, the authors analyze blood proteins and brain MRI data one year after mild COVID-19, revealing distinct neurodegenerative processes in PASC patients with cognitive problems, such as cortical thinning, brain iron deposition, enlarged choroid plexus, and increased blood neuronal/glial injury markers, compared to other-PASC.

Amyloid-β (Aβ)-containing extracellular plaques and hyperphosphorylated tau-loaded intracellular neurofibrillary tangles are neuropathological hallmarks of Alzheimer's disease (AD). Although Aβ exerts neuropathogenic activity through tau, the mechanistic link between Aβ and tau pathology remains unknown. Here, we showed that the FcγRIIb-SHIP2 axis is critical in Aβ1-42-induced tau pathology. Fcgr2b knockout or antagonistic FcγRIIb antibody inhibited Aβ1-42-induced tau hyperphosphorylation and rescued memory impairments in AD mouse models. FcγRIIb phosphorylation at Tyr273 was found in AD brains, in neuronal cells exposed to Aβ1-42, and recruited SHIP2 to form a protein complex. Consequently, treatment with Aβ1-42 increased PtdIns(3,4)P2 levels from PtdIns(3,4,5)P3 to mediate tau hyperphosphorylation. Further, we found that targeting SHIP2 expression by lentiviral siRNA in 3xTg-AD mice or pharmacological inhibition of SHIP2 potently rescued tau hyperphosphorylation and memory impairments. Thus, we concluded that the FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau pathology by dysregulating PtdIns(3,4)P2 metabolism, providing insight into therapeutic potential against AD. In Alzheimer’s disease, damage to neurons in the brain gradually causes memory loss and difficulties with thinking. The main hallmarks of this damage are seen in the accumulation of proteins in and around neurons. First, a protein called amyloid beta forms aggregates outside the cell. This appears to lead to the build up of an abnormal form of a protein called tau inside the cell. These abnormal tau proteins have excessive numbers of phosphate groups attached to them, and so are known as “hyperphosphorylated”. The molecular mechanism underlying amyloid beta’s role in the hyperphosphorylation of tau proteins was not known. Amyloid beta binds to many different receptor proteins – including one called Fc gamma receptor IIb – on the surface of neurons. Kam, Park et al. investigated whether interactions between amyloid beta and Fc gamma receptor IIb might regulate the phosphorylation of tau within neurons. Adding amyloid beta to mouse neurons caused tau proteins to become hyperphosphorylated. However, removing Fc gamma receptor IIb from the neurons, or stopping it from binding to amyloid beta, abolished this effect. When amyloid beta was bound to Fc gamma receptor IIb, the receptor became phosphorylated. This in turn triggered a series of further phosphorylation events, culminating in an increase in the level of a molecule that relays signals from cell receptors – called SHIP2 – inside the neurons. This molecule increases tau phosphorylation when added to neurons. Reducing the activity or amount of SHIP2 in mice that present the symptoms of Alzheimer’s disease reduced the hyperphosphorylation of the tau protein in their neurons and restored their memory to normal levels. Kam, Park et al. also looked at samples taken from the brains of human Alzheimer's disease patients. Unlike samples taken from people without Alzheimer’s disease, neurons in these samples contain both phosphorylated Fc gamma receptor IIb and hyperphosphorylated tau proteins. By uncovering the molecules that link amyloid beta with tau hyperphosphorylation, Kam, Park et al.’s results suggest new targets for therapies to treat the symptoms of Alzheimer’s disease. More research is now needed to investigate whether this could lead to the design of new drugs.

Amyloid‐β (Aβ) plays a crucial role in Alzheimer's disease pathogenesis. Understanding how Aβ overexpression alters the proteome of individual brain cell types is essential but challenging due to the nature of brain tissue, which contains intermingled various cell types. The current methods for cell‐type‐specific proteomics either require genetic modifications or complex cell isolation, limiting their use. This study introduces a novel method, in situ cell‐type‐specific proteome analysis using antibody‐mediated biotinylation (iCAB), which applies immunohistochemistry with biotin‐tyramide to target cell‐specific proteins directly in tissue. Applied to 5xFAD mice, iCAB enables us to identify ≈8000 cell‐type‐specific proteomes with significantly more differentially expressed proteins than traditional bulk proteome methods, pinpointing unique pathways such as mRNA processing, calcium regulation, and phagocytosis for neurons, astrocytes, and microglia, respectively. This study reports in‐depth the cell‐type‐specific brain proteome landscape of the human Aβ overexpression mouse model for the first time using an innovative tool that is powerful, straightforward, and applicable to both animal models and human tissues, without the need for prior genetic alterations. In situ Cell‐type‐specific proteome Analysis using antibody‐mediated Biotinylation (iCAB) is a method that directly targets and analyzes proteins in specific cell types within tissue. Applied to 5xFAD mice, iCAB identifies ≈8000 cell‐type‐specific proteins, revealing unique pathways in neurons, astrocytes, and microglia. This technique offers a powerful and straightforward approach applicable to both animal models and human tissues.

The application of extracellular vesicles (EVs) as vehicles for anti‐Parkinson's agents represents a significant advance, yet their clinical translation is hampered by challenges in efficient brain delivery and complex blood‐brain barrier (BBB) targeting strategies. In this study, we engineered dopamine onto the surface of adipose‐derived stem cell EVs (Dopa‐EVs) utilizing a facile, two‐step cross‐linking approach. This engineering enhanced neuronal uptake of the EVs in primary neurons and neuroblastoma cells, a process shown to be competitively inhibited by dopamine pretreatment and dopamine receptor antibodies. Notably, Dopa‐EVs demonstrated increased brain accumulation in mouse Parkinson's disease (PD) models. Therapeutically, Dopa‐EVs administration led to the rescue of dopaminergic neuronal loss and amelioration of behavioural deficits in both 6‐hydroxydopamine (6‐OHDA) and α‐Syn PFF‐induced PD models. Furthermore, we observed that Dopa‐EVs stimulated autophagy evidenced by the upregulation of Beclin‐1 and LC3‐II. These findings collectively indicate that surface modification of EVs with dopamine presents a potent strategy for targeting dopaminergic neurons in the brain. The remarkable therapeutic potential of Dopa‐EVs, demonstrated in PD models, positions them as a highly promising candidate for PD treatment, offering a significant advance over current therapeutic modalities.

Retinitis pigmentosa (RP) and associated inherited retinal diseases (IRDs) are caused by rod photoreceptor degeneration, necessitating therapeutics promoting rod photoreceptor survival. To address this, we tested compounds for neuroprotective effects in multiple zebrafish and mouse RP models, reasoning drugs effective across species and/or independent of disease mutation may translate better clinically. We first performed a large-scale phenotypic drug screen for compounds promoting rod cell survival in a larval zebrafish model of inducible RP. We tested 2934 compounds, mostly human-approved drugs, across six concentrations, resulting in 113 compounds being identified as hits. Secondary tests of 42 high-priority hits confirmed eleven lead candidates. Leads were then evaluated in a series of mouse RP models in an effort to identify compounds effective across species and RP models, that is, potential pan-disease therapeutics. Nine of 11 leads exhibited neuroprotective effects in mouse primary photoreceptor cultures, and three promoted photoreceptor survival in mouse rd1 retinal explants. Both shared and complementary mechanisms of action were implicated across leads. Shared target tests implicated parp1 -dependent cell death in our zebrafish RP model. Complementation tests revealed enhanced and additive/synergistic neuroprotective effects of paired drug combinations in mouse photoreceptor cultures and zebrafish, respectively. These results highlight the value of cross-species/multi-model phenotypic drug discovery and suggest combinatorial drug therapies may provide enhanced therapeutic benefits for RP patients. Photoreceptors are the cells responsible for vision. They are part of the retina: the light-sensing tissue at the back of the eye. They come in two types: rods and cones. Rods specialise in night vision, while cones specialise in daytime colour vision. The death of these cells can cause a disease, called retinitis pigmentosa, that leads to vision loss. Symptoms often start in childhood with a gradual loss of night vision. Later on, loss of cone photoreceptors can lead to total blindness. Unfortunately, there are no treatments available that protect photoreceptor cells from dying. Research has identified drugs that can protect photoreceptors in animal models, but these drugs have failed in humans. The classic way to look for new treatments is to find drugs that target molecules implicated in a disease, and then test them to see if they are effective. Unfortunately, many drugs identified in this way fail in later stages of testing, either because they are ineffective, or because they have unacceptable side effects. One way to reverse this trend is to first test whether a drug is effective at curing a disease in animals, and later determining what it does at a molecular level. This could reveal whether drugs can protect photoreceptors before research to discover their molecular targets begins. Tests like this across different species could maximise the chances of finding a drug that works in humans, because if a drug works in several species, it is more likely to have shared target molecules across species. Applying this reasoning, Zhang et al. tested around 3,000 drug candidates for treating retinitis pigmentosa in a strain of zebrafish that undergoes photoreceptor degeneration similar to the human disease. Most of these drug candidates already have approval for use in humans, meaning that if they were found to be effective for treating retinitis pigmentosa, they could be fast-tracked for use in people. Zhang et al. found three compounds that helped photoreceptors survive both in zebrafish and in retinas grown in the laboratory derived from a mouse strain with degeneration similar to retinitis pigmentosa. Tests to find out how these three compounds worked at the molecular level revealed that they interfered with a protein that can trigger cell death. The tests also found other promising compounds, many of which offered increased protection when combined in pairs. Worldwide there are between 1.5 and 2.5 million people with retinitis pigmentosa. With this disease, loss of vision happens slowly, so identifying drugs that could slow or stop the process could help many people. These results suggest that placing animal testing earlier in the drug discovery process could complement traditional target-based methods. The compounds identified here, and the information about how they work, could expand potential treatment research. The next step in this research is to test whether the drugs identified by Zhang et al. protect mammals other than mice from the degeneration seen in retinitis pigmentosa.