Peripheral nerves have an intrinsic capacity for regeneration after traumatic injury, with Schwann cells (SCs) playing a central role in orchestrating this complex process. Critical components of successful regeneration include SC reprogramming into repair SCs, debris removal and metabolic adaptations. Up to now, there are no pharmacological treatments available in the clinics to improve nerve regeneration. In this study, we investigated peroxisome proliferator-activated receptor gamma (PPARɣ) as a therapeutic target in the context of nerve regeneration, since we previously found this transcription factor to be involved in SC reprograming and metabolic adaptations. Therefore, we used a mouse model of sciatic nerve crush injury and applied the PPARɣ agonist pioglitazone (PIO) in two different treatment paradigms: (i) acutely after injury (0-5 days post injury) and (ii) delayed (5-21 days post injury), thereby addressing different phases of regeneration. Our findings revealed that PIO treatment immediately following nerve injury (first treatment paradigm) disrupted SC transition into the repair phenotype and diminished the physiological inflammatory response. As a consequence, axonal and myelin debris clearance was delayed, ultimately resulting in impaired axonal outgrowth and nerve regeneration. In the second treatment paradigm (PIO administration starting five days after injury) SCs had already acquired the repair phenotype and immune cell infiltration had taken place when PIO administration started. There, PIO promoted axonal regeneration, enhanced remyelination, and improved functional recovery. Importantly, PIO treatment increased mitochondrial content in neurons and SCs. In addition, delayed application of PIO induced lipid metabolism, glycolysis and ATP production in SCs, leading to the assumption that improved metabolic conditions mediate enhanced nerve regeneration in this treatment paradigm. These findings show that depending on the timing of PIO treatment, PPARɣ can serve as a potential therapeutic agent to improve nerve regeneration by promoting key metabolic adaptations.

Protein truncating variants (PTVs) in are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare missense variants is unclear.

Pathogenic tau accumulation drives neurodegeneration in Alzheimer's disease (AD). Enhancing the aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive.

Novel plasma assays enabled accurate blood-based biomarkers for neurodegenerative diseases with minimally invasive options for clinical use. Large-scale studies encompassing multiple neurodegenerative diseases using novel multiplex platforms are essential to uncover disease-specific biomarkers and pathways. We generated and analyzed plasma biomarker data using the NULISAseq™ CNS Panel from 3,232 participants with Alzheimer disease (AD), Dementia with Lewy bodies (DLB), Frontotemporal dementia (FTD), Parkinson disease (PD) and cognitively unimpaired individuals, from the Charles F. and Joanne Knight Alzheimer Disease Research Center. We identified proteins associated with disease status and AD-related phenotypes (Clinical Dementia Rating®, CSF Aβ42/Aβ40, Amyloid-PET, and Tau-PET). These proteins were used to identify disease-specific biomarkers and perform pathway analyses. We identified 81 proteins associated with AD, 21 with DLB, four with FTD, and 52 with PD after multiple test correction. Disease comparison showed that PD and DLB had the highest similarity, followed by AD and DLB. Concurrently, each disease also presented disease-specific signatures. Some AD-specific proteins included p-tau217; MSLN and SAA1 were specific to DLB, and FLT1 and PARK7 to PD. We also identified eight proteins associated with Amyloid-PET, eight with Tau-PET, 14 with CSF Aβ42/40 ratio, and 72 with CDR, some of which were specific to each phenotype. We used a data-driven approach to identify the p-tau217 cut-off for biomarker positivity. Plasma p-tau217 achieved an AUC of 0.81 (95% CI: 0.79-0.83) for AD diagnosis and 0.96 (95% CI: 0.94-0.98) for Amyloid positivity. P-tau217 had 93.77% agreement with Amyloid-PET status. Proteins associated with AD were enriched in protein-lipid complex binding pathway, whereas PD associated proteins were enriched in laminin-related pathways. FTD associated proteins were enriched in cytoskeleton proteins. This is the largest plasma NULISA CNS study performed till date and covers the four major neurodegenerative diseases: AD, PD, DLB and FTD. We validated the high classification accuracy of the NULISA plasma p-tau217 and its strong correlation with Amyloid-PET status. We also identified disease-specific proteins that could enhance differential diagnosis. These findings highlight the potential of the NULISA platform as a reliable quantitative tool for research and clinical applications in neurodegenerative diseases.

Emerging evidence implicates that tau SUMOylation disrupts tau homeostasis. Death-associated protein kinase 1 (DAPK1) has been shown to affect tau phosphorylation and accumulation. The sentrin-specific protease 1 (SENP1) is important for protein SUMOylation, and is a potential substrate of DAPK1. However, whether DAPK1 regulates tau SUMOylation and proteostasis through modulating SENP1 remains elusive.

Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer's disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson's disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer's disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.

M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43 transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1 transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.

Synaptic homeostasis, maintained by microglia and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.

Glaucoma Research Foundation's third Catalyst for a Cure team (CFC3) was established in 2019 to uncover new therapies for glaucoma, a leading cause of blindness. In the 2021 meeting "Solving Neurodegeneration," (detailed in Mol Neurodegeneration 17(1), 2022) the team examined the failures of investigational monotherapies, issues with translatability, and other significant challenges faced when working with neurodegenerative disease models. They emphasized the need for novel, humanized models and proposed identifying commonalities across neurodegenerative diseases to support the creation of pan-neurodegenerative disease therapies. Since then, the fourth Catalyst for a Cure team (CFC4) was formed to explore commonalities between glaucoma and other neurodegenerative diseases. This review summarizes outcomes from the 2023 "Solving Neurodegeneration 2" meeting, a forum for CFC3 and CFC4 to share updates, problem solve, plan future research collaborations, and identify areas of unmet need or opportunity in glaucoma and the broader field of neurodegenerative disease research.

With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes.

The potential neuroprotective effects of antidiabetic treatments have been largely assessed in Alzheimer's disease (AD) and AD-like dementia models, with or without metabolic disorders. In this Line, these effects Have also been addressed in wide population-based studies or in patients with mild cognitive impairment, AD, diabetes or combined pathologies. Most common treatments include glucagon-like peptide 1 receptor agonists; thiazolidinediones; biguanides; sulphonylureas; dipeptidyl peptidase-4 inhibitors, insulin, amylin and others. To assess their impact, we have conducted a systematic search in PubMed to Identify studies addressing the effect of Antidiabetic treatments on AD or AD-like dementia preclinical models And clinical studies, yielding 3560 research items. After screening titles And abstracts, 380 papers met eligibility criteria (original full-text articles, written in English, focused on AD or AD-like dementia, involving antidiabetic treatments, containing data on neuropathological AD markers and/or cognitive function, and conducted in vivo or ex vivo), And 25 additional papers were added through citations, resulting in a Total of 405 primary research articles published between 1996 And 2024. We have reviewed the effects of antidiabetic treatments on tau pathology, neuronal health, oxidative stress and neuroinflammation, vascular alterations, implicated signaling pathways and cognitive function in AD and AD-like dementia preclinical models and patients. Overall, antidiabetic medications represent a promising therapeutic strategy to tackle neurodegeneration and cognitive decline in AD preclinical models. Nevertheless, further research is needed to optimize their clinical effectiveness.

The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.

Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could serve as a central hub of detection and regulation of body state changes. In addition, improving understanding of how microglia respond to peripheral cues will allow for improved preclinical experimental design. As peripheral cues have the potential to be more readily manipulated than central cues, these interactions also have implications for the treatment of many diseases and neurodegenerative disorders.

Various plasma phosphorylated tau species have been shown to be associated with amyloid-β (Aβ) PET and Tau PET in Alzheimer’s disease (AD), but whether APOE ε4 affects the interaction between glial fibrillary acidic protein (GFAP) and phosphorylated tau (pTau), and whether a three-way interaction exists among APOE ε4, GFAP, and pTau that influences AD progression remain unclear.

The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1-4), with a decline at later stages (5-6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.