Vulnerable Neuronal Populations Research Articles

Short Peptides Protect Fibroblast-Derived Induced Neurons from Age-Related Changes.

Neurons become more vulnerable to stress factors with age, which leads to increased oxidative DNA damage, decreased activity of mitochondria and lysosomes, increased levels of p16, decreased LaminB1 proteins, and the depletion of the dendritic tree. These changes are exacerbated in vulnerable neuronal populations during the development of neurodegenerative diseases. Glu-Asp-Arg (EDR) and Lys-Glu-Asp (KED), and Ala-Glu-Asp-Gly (AEDG) peptides have previously demonstrated neuroprotective effects in various models of Alzheimer's disease. In this study, we investigated the influence of EDR, KED, and AEDG peptides on the aging of fibroblast-derived induced neurons. We used a new in vitro cellular model of human neuronal aging based on the transdifferentiation of aged dermal fibroblasts from elderly donors into induced cortical neurons. All peptides promote the arborization of the dendritic tree, increasing both the number of primary processes and the total length of dendrites. Tripeptides have no effect on the activity of mitochondria and lysosomes and the level of p16 protein in induced neurons. EDR peptide reduces oxidative DNA damage in induced neurons derived from elderly donor fibroblasts. Short peptides partially protect induced neurons from age-related changes and stimulate dendritogenesis in neurons. They can be recommended for use as neuroprotective agents.

Tau load in select brainstem neurons predicts the severity and nature of balance deficits in the absence of cell death.

Patients with tauopathies present with profoundly different clinical symptoms 1 , even within the same disorder 2 . A central hypothesis in the field, well-supported by biomarker studies 3,4 and post-mortem pathology 5-7 , is that clinical heterogeneity reflects differential degeneration of vulnerable neuronal populations responsible for specific neurological functions. Recent work has revealed mechanisms underlying susceptibility of particular cell types 8-10 , but relating tau load to disrupted behavior - es- pecially before cell death - requires a targeted circuit-level approach. Here we studied two distinct balance behaviors in larval zebrafish 11 expressing a human 0N/4R-tau allele 12 in select populations of evolutionarily-conserved and well-characterized brainstem vestibular circuits 13,14 . We observed that human tau load predicted the severity of circuit-specific deficits in posture and navigation in the ab- sence of cell death. Targeting expression to either mid- or hindbrain balance neurons recapitulated these particular deficits in posture and navigation. By parametrically linking tau load in specific neu- rons to early behavioral deficits, our work moves beyond cell type to close the gap between pathological and neurological conceptions of tauopathy.

Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.

Autophagy, the major lysosomal pathway for degrading damaged or obsolete constituents, protects neurons by eliminating toxic organelles and peptides, restoring nutrient and energy homeostasis, and inhibiting apoptosis. These functions are especially vital in neurons, which are postmitotic and must survive for many decades while confronting mounting challenges of cell aging. Autophagy failure, especially related to the declining lysosomal ("phagy") functions, heightens the neuron's vulnerability to genetic and environmental factors underlying Alzheimer's disease (AD) and other late-age onset neurodegenerative diseases. Components of the global autophagy-lysosomal pathway and the closely integrated endolysosomal system are increasingly implicated as primary targets of these disorders. In AD, an imbalance between heightened autophagy induction and diminished lysosomal function in highly vulnerable pyramidal neuron populations yields an intracellular lysosomal build-up of undegraded substrates, including APP-βCTF, an inhibitor of lysosomal acidification, and membrane-damaging Aβ peptide. In the most compromised of these neurons, β-amyloid accumulates intraneuronally in plaque-like aggregates that become extracellular senile plaques when these neurons die, reflecting an "inside-out" origin of amyloid plaques seen in human AD brain and in mouse models of AD pathology. In this review, the author describes the importance of lysosomal-dependent neuronal cell death in AD associated with uniquely extreme autophagy pathology (PANTHOS) which is described as triggered by lysosomal membrane permeability during the earliest "intraneuronal" stage of AD. Effectors of other cell death cascades, notably calcium-activated calpains and protein kinases, contribute to lysosomal injury that induces leakage of cathepsins and activation of additional death cascades. Subsequent events in AD, such as microglial invasion and neuroinflammation, induce further cytotoxicity. In major neurodegenerative disease models, neuronal death and ensuing neuropathologies are substantially remediable by reversing underlying primary lysosomal deficits, thus implicating lysosomal failure and autophagy dysfunction as primary triggers of lysosomal-dependent cell death and AD pathogenesis and as promising therapeutic targets.

Single-cell multiregion dissection of Alzheimer’s disease

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood1–3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology.

Microalgae Octapeptide IIAVEAGC Alleviates Oxidative Stress and Neurotoxicity in 6-OHDA-Induced SH-SY5Y Cells by Regulating the Nrf2/HO-1and Jak2/Stat3 Pathways.

Neurodegenerative diseases are characterized by the progressive loss of selectively vulnerable populations of neurons, and many factors are involved in its causes. Neurotoxicity and oxidative stress, are the main related factors. The octapeptide Ile-Ile-Ala-Val-Glu-Ala-Gly-Cys (IEC) was identified from the microalgae Isochrysis zhanjiangensis and exhibited potential anti-oxidative stress activity. In this study, the stability of α-synaptic protein binding to IEC was modeled using molecular dynamics, and the results indicated binding stabilization within 60 ns. Oxidative stress in neurons is the major cause of α-synaptic protein congestion. Therefore, we next evaluated the protective effects of IEC against oxidative stress and neurotoxicity in 6-ohdainduced Parkinson's disease (PD) model SH-SY5Y cells in vitro. In oxidative stress, IEC appeared to increase the expression of the antioxidant enzymes HO-1 and GPX through the antioxidant pathway of Nrf2, and molecular docking of IEC with Nrf2 and GPX could generate hydrogen bonds. Regarding apoptosis, IEC protected cells by increasing the Bcl-2/Bax ratio, inhibiting the caspase cascade, acting on p53, and modulating the Jak2/Stat3 pathway. The results indicated that IEC exerted neuroprotective effects through the inhibition of α-synaptic protein aggregation and antioxidant activity. Therefore, microalgal peptides have promising applications in the prevention and treatment of neurodegenerative diseases.

ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease

In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.

NETS‐seq advances the understanding of neuronal vulnerability in AD progression facilitating the identification of novel therapeutic targets at the single cell type level

AbstractBackgroundAlzheimer’s Disease (AD) is a complex, heterogeneous, and multi‐factorial disease of predominantly the aging population. Throughout disease progression, different brain regions and cell types within each region show varying levels of resilience to ongoing disease pathology. A better understanding of the biological properties of different cell types and an integrated analysis approach that incorporates information about the interplay between cell type vulnerability, pathological deposits, and inflammatory signatures are required for the development of novel therapeutics that delay the onset or slow the progression of AD.MethodCerevance has developed a proprietary Nuclear Enriched Transcript Sort sequencing (NETS‐seq) method that provides deep molecular insight into the dynamics of the brains of early‐stage AD, late‐stage AD, and non‐neurodegenerative age‐matched control donors at the individual cell type level. Machine learning methodologies based on gene expression were employed to stratify donors across the disease continuum and to identify gene changes associated with disease progression.ResultNETS‐seq enabled us to profile more than a dozen distinct cortical cell types. These data show that many known AD risk genes, as well as many lesser described genes, change in expression in disease. We have also used pseudotime trajectory analysis to rank donors across disease progression from control to early‐ and late‐stage AD. Comparisons made across different cell types within the same brain region and the same cell types from different brain regions, have identified genes that may be contributing to AD progression at different stages of disease. These genes may contribute to ongoing neuronal vulnerability.ConclusionWe have produced highly reproducible molecular profiles from neuronal (and glial) cell types from the human brain and demonstrated that many genes are specifically expressed in cortical neuronal subtypes and change across the AD disease continuum. Identifying changes in the transcriptomic signatures of vulnerable neuronal populations at different stages of disease has enabled the identification and selection of novel targets for AD drug discovery.

Multimodal and multiregional atlas of Alzheimer’s disease changes

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia. The progression of AD throughout the brain follows a stereotypical pattern that can be described by the quantification of histopathological changes in several brain regions. As part of The Seattle Alzheimer’s Disease Cell Atlas (SEA‐AD, https://sea-ad.org), we previously quantified pathological proteins in the middle temporal gyrus (MTG) and used them to describe disease progression, vulnerable cell types, and the MTG molecular changes related to diseaseMethodIn this work, we expanded our results and undertook a comparative approach. We measured a battery of neuropathological proteins (staining NeuN, AT8, IBA1, GFAP, 6e10, pTDP43, and a‐Syn immunoreactivity, and analyzing them with machine learning) in the middle temporal gyrus, the middle frontal gyrus, and medial entorhinal cortex in 84 donors. In addition, we undertook a multimodal single‐cell analysis of such regions, profiling cells using single‐cell RNA‐seq, ATAC‐seq, Multiome, and spatial transcriptomic.Borrowing from our hierarchically resolved cell types in MTG, based on the BRAIN initiative cell type reference, we used machine learning algorithms to create multimodal cell type maps across regions. We used Bayesian statistics to identify differentially accessible regulatory elements, link them to the affected genes and the regulatory transcriptional machinery binding in such elements.ResultWe identified regional vulnerable neuronal populations and a core set of transcriptionally similar cell types susceptible to disease across the cortex. We created a cortex‐wide disease progression map combining neuropathological data from our three profiled regions with latent Bayesian statistical algorithms. In each area, we developed an AD pseudo‐progression timescale that describes the burden of disease in the area and, next, combined all areas to create a cortex‐wide holistic pseudo‐progression. We used the mapped cell types and our developed scale to synchronize changes occurring in each patient, describing abundances, gene expression, and chromatin accessibility modifications.ConclusionThe progression scale developed in this study serves as a reference to align changes across brain regions and, in the future, to reconcile differences across cohorts.

Longitudinal single-cell transcriptional dynamics throughout neurodegeneration in SCA1

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration.

Butanolides and Butenolides from a Marine-Derived Streptomyces sp. Exert Neuroprotective Activity through Activation of the TrkB Neurotrophin Receptor.

Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number of bacterial strains isolated from East Mediterranean marine sediments and macroorganisms were evaluated for their activity on TrkB-expressing cells. Among them, the actinobacterial strain Streptomyces sp. BI0788, exhibiting neuroprotective activity in vitro, was selected and cultivated in large-scale. The chemical analysis of its organic extract resulted in the isolation of four new butanolides (1, 4-6), along with two previously reported butanolides (2 and 3) and eight previously reported butenolides (7-14). Compounds 2-4 and 7-14 were evaluated for their neuroprotective effects on TrkB-expressing NIH-3T3 cells. Among them, metabolites 3, 4, 7, 10, 11, 13 and 14 exhibited significant protective activity on the aforementioned cells through the activation of TrkB, the high-affinity receptor for the Brain-Derived Neurotrophic Factor (BDNF), which is well known to play a crucial role in neuronal cell survival and maintenance.

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1

Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using invivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.

Emerging Roles of Signal Transduction Pathways in Neurodegenerative Diseases. Hunting New Possible Therapeutic Molecular Targets

Illnesses following the degeneration of the nervous system can occur due to aging or genetic mutations and represent a clinical concern. In neurodegenerative diseases, loss of neuronal structure and functions mainly causes cognitive impairment, representing an increasing social burden. In neurodegenerative diseases, the progressive loss of vulnerable populations of neurons in specific regions of the central nervous system was traced to different pathological events, such as misfolded proteins’ accumulation, abnormalities in proteasomes or phagosomes, as well as anomalies in lysosomes or mitochondria. Many research efforts identified important events involved in neurodegeneration, but the complex pathogenesis of neurodegenerative diseases is far from being fully elucidated. More recently, insights into the signal transduction pathways acting in the nervous system contributed to unveiling some molecular mechanisms triggering neurodegeneration. Abnormalities in the intra- or inter-cellular signaling were described to be involved in the pathogenesis of neurodegenerative disease. Understanding the signal transduction pathways that impact the nervous system homeostasis can offer a wide panel of potential targets for modulating therapeutic approaches. The present review will discuss the main signal transduction pathways involved in neurodegenerative disorders.

TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.

Phosphorylated tau (p-tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA-binding protein (pTDP-43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571-585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811-824). Current staging schemes for pTDP-43 in AD and primary age-related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP-43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p-tau and pTDP-43 co-localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP-43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior-lateral subfields showed the highest semi-quantitative pTDP-43 density scores, while the anterior-medial subfields had the lowest. On the rostrocaudal axis, pTDP-43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior-most level (p < 0.050). Further, we showed the relationship between pTDP-43 and p-tau in these regions at pathology-positive but clinically silent stages. P-tau and pTDP-43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P-tau burden was consistently higher than pTDP-43 at every anterior-posterior level and in most EC subfields. These findings highlight pTDP-43 burden heterogeneity within the EC and the posterior-lateral subfields as the most vulnerable regions within stage II of the current pTDP-43 staging schemes for AD and PART. The EC is a point of convergence for p-tau and pTDP-43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention.

Sex and Gender Differences in Neurodegenerative Diseases: Challenges for Therapeutic Opportunities.

The term "neurodegenerative diseases" (NDs) identifies a group of heterogeneous diseases characterized by progressive loss of selectively vulnerable populations of neurons, which progressively deteriorates over time, leading to neuronal dysfunction. Protein aggregation and neuronal loss have been considered the most characteristic hallmarks of NDs, but growing evidence confirms that significant dysregulation of innate immune pathways plays a crucial role as well. NDs vary from multiple sclerosis, in which the autoimmune inflammatory component is predominant, to more "classical" NDs, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Of interest, many of the clinical differences reported in NDs seem to be closely linked to sex, which may be justified by the significant changes in immune mechanisms between affected females and males. In this review, we examined some of the most studied NDs by looking at their pathogenic and phenotypical features to highlight sex-related discrepancies, if any, with particular interest in the individuals' responses to treatment. We believe that pointing out these differences in clinical practice may help achieve more successful precision and personalized care.

Identification of gene networks mediating regional resistance to tauopathy in late-onset Alzheimer's disease.

Neurofibrillary lesions composed of tau protein aggregates are defining hallmarks of Alzheimer's Disease. Despite tau filaments appearing to spread between networked brain regions in a prion-like manner, certain areas including cerebellum resist trans-synaptic spread of tauopathy and degeneration of their constituent neuronal cell bodies. To identify molecular correlates of resistance, we derived and implemented a ratio of ratios approach for disaggregating gene expression data on the basis of regional vulnerability to tauopathic neurodegeneration. When applied to vulnerable pre-frontal cortex as an internal reference for resistant cerebellum, the approach segregated adaptive changes in expression into two components. The first was enriched for neuron-derived transcripts associated with proteostasis including specific members of the molecular chaperone family and was unique to resistant cerebellum. When produced as purified proteins, each of the identified chaperones depressed aggregation of 2N4R tau in vitro at sub-stoichiometric concentrations, consistent with the expression polarity deduced from ratio of ratios testing. In contrast, the second component enriched for glia- and microglia-derived transcripts associated with neuroinflammation, segregating these pathways from susceptibility to tauopathy. These data support the utility of ratio of ratios testing for establishing the polarity of gene expression changes with respect to selective vulnerability. The approach has the potential to identify new targets for drug discovery predicated on their ability to promote resistance to disease in vulnerable neuron populations.

Functions and dysfunctions of oligodendrocytes in neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are characterized by the progressive loss of selectively vulnerable populations of neurons, which is responsible for the clinical symptoms. Although degeneration of neurons is a prominent feature that undoubtedly contributes to and defines NDD pathology, it is now clear that neuronal cell death is by no means mediated solely by cell-autonomous mechanisms. Oligodendrocytes (OLs), the myelinating cells of the central nervous system (CNS), enable rapid transmission of electrical signals and provide metabolic and trophic support to neurons. Recent evidence suggests that OLs and their progenitor population play a role in the onset and progression of NDDs. In this review, we discuss emerging evidence suggesting a role of OL lineage cells in the pathogenesis of age-related NDDs. We start with multiple system atrophy, an NDD with a well-known oligodendroglial pathology, and then discuss Alzheimer's disease (AD) and Parkinson's disease (PD), NDDs which have been thought of as neuronal origins. Understanding the functions and dysfunctions of OLs might lead to the advent of disease-modifying strategies against NDDs.

Tau pathology vulnerable neuronal subpopulation in Alzheimer’s disease

AbstractBackgroundTau pathology is known as a primary driver of neurodegeneration in Alzheimer’s disease (AD). Understanding its underlying molecular mechanism is critical in expanding our knowledge of AD pathogenesis and developing novel AD therapeutic strategies. However, interrogating tau induced neurotoxicity mechanisms has been difficult due to heterogeneous susceptibility of neurons to tau pathology. Here, we aim to identify the most vulnerable neuronal subpopulation to tau pathology in AD and reveal more clear molecular mechanisms of tau induced neuro‐toxicity/degeneration by analyzing gene expression changes in the vulnerable population.MethodWe performed single nuclei RNA sequencing and tau biochemistry from same tissue blocks of the same AD patients (5 brain regions of 32 AD donors with various Braak stages). About 1.5x106 neurons were enriched in total by NeuN antibody‐based flow cytometry sorting and these cells were clustered into 15 neuronal subpopulations based on their similarity in gene expression. We tested for association between relative neuronal population abundance and tau pathology readouts (phospho‐T231 ELISA, HT7‐HT7 SIMOA and HEK seeding). Based on the strength of correlation, we identified the neuronal subpopulation that reduces relative abundance in association with its tau pathology.ResultWe identified a tau vulnerable neuronal population that showed strong negative correlation between its relative abundance and tau pathology readouts in BA20 and BA46. The population was one of largest excitatory subpopulation distinguished by marker genes, CBLN2 and LINC00507. This outcome was supported by multiple published transcriptomics studies and histologically validated by multiplexed in situ hybridization and immunohistochemistry. Differential gene expression analysis of the vulnerable neuronal population identified a list of genes that potentially links tau pathology and neuronal death.ConclusionThis study with large number of captured neurons for single cell transcriptomics and quantitative tau pathology readout for direct comparison to transcriptomics data enabled the discovery of a vulnerable neuronal subpopulation in more precise manner and revealed genes related to tau associated neurotoxicity more clearly. This result serves as a great starting point to further interrogate fundamental mechanisms of tau‐driven neurodegeneration in AD and accelerate therapeutic target and biomarker discovery.

Oxytocin in Huntington's disease and the spectrum of amyotrophic lateral sclerosis-frontotemporal dementia.

Neurodegenerative disorders (NDDs) such as Huntington’s disease (HD) and the spectrum of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by progressive loss of selectively vulnerable populations of neurons. Although often associated with motor impairments, these NDDs share several commonalities in early symptoms and signs that extend beyond motor dysfunction. These include impairments in social cognition and psychiatric symptoms. Oxytocin (OXT) is a neuropeptide known to play a pivotal role in the regulation of social cognition as well as in emotional behaviors such as anxiety and depression. Here, we present an overview of key results implicating OXT in the pathology of HD, ALS and FTD and seek to identify commonalities across these NDDs. OXT is produced in the hypothalamus, a region in the brain that during the past decade has been shown to be affected in HD, ALS, and FTD. Several studies using human post-mortem neuropathological analyses, measurements of cerebrospinal fluid, experimental treatments with OXT as well as genetic animal models have collectively implicated an important role of central OXT in the development of altered social cognition and psychiatric features across these diseases. Understanding central OXT signaling may unveil the underlying mechanisms of early signs of the social cognitive impairment and the psychiatric features in NDDs. It is therefore possible that OXT might have potential therapeutic value for early disease intervention and better symptomatic treatment in NDDs.

Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration

Multiple neurotoxic proteinopathies co-exist within vulnerable neuronal populations in all major neurodegenerative diseases. Interactions between these pathologies may modulate disease progression, suggesting they may constitute targets for disease-modifying treatments aiming to slow or halt neurodegeneration. Pairwise interactions between superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and ubiquitin-binding protein 62/sequestosome 1 (p62) proteinopathies have been reported in multiple transgenic cellular and animal models of amyotrophic lateral sclerosis (ALS), however corresponding examination of these relationships in patient tissues is lacking. Further, the coalescence of all three proteinopathies has not been studied in vitro or in vivo to date. These data are essential to guide therapeutic development and enhance the translation of relevant therapies into the clinic. Our group recently profiled SOD1 proteinopathy in post-mortem spinal cord tissues from familial and sporadic ALS cases, demonstrating an abundance of structurally-disordered (dis)SOD1 conformers which become mislocalized within these vulnerable neurons compared with those of aged controls. To explore any relationships between this, and other, ALS-linked proteinopathies, we profiled TDP-43 and p62 within spinal cord motor neurons of the same post-mortem tissue cohort using multiplexed immunofluorescence and immunohistochemistry. We identified distinct patterns of SOD1, TDP43 and p62 co-deposition and subcellular mislocalization between motor neurons of familial and sporadic ALS cases, which we primarily attribute to SOD1 gene status. Our data demonstrate co-deposition of p62 with mutant and wild-type disSOD1 and phosphorylated TDP-43 in familial and sporadic ALS spinal cord motor neurons, consistent with attempts by p62 to mitigate SOD1 and TDP-43 deposition. Wild-type SOD1 and TDP-43 co-deposition was also frequently observed in ALS cases lacking SOD1 mutations. Finally, alterations to the subcellular localization of the three proteins were tightly correlated, suggesting close relationships between the regulatory mechanisms governing the subcellular compartmentalization of these proteins. Our study is the first to profile spatial relationships between SOD1, TDP-43 and p62 pathologies in post-mortem spinal cord motor neurons of ALS patients, previously only studied in vitro. Our findings suggest interactions between these three key ALS-linked proteins are likely to modulate the formation of their respective proteinopathies, and perhaps the rate of motor neuron degeneration, in ALS patients.

Unique molecular features and cellular responses differentiate two populations of motor cortical layer 5b neurons in a preclinical model of ALS.

SUMMARYMany neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding the unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type-specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Oxphos and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell-type-specific processes in neurodegenerative disease.