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Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma protein (FUS), molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

Neurodegenerative diseases are characterised by selective dysfunction and progressive loss of synapses and neurons associated with pathologically altered proteins that deposit primarily in the human brain and spinal cord. Recent discoveries have identified a spectrum of distinct immunohistochemically and biochemically detectable proteins, which serve as a basis for protein-based disease classification. Diagnostic criteria have been updated and disease staging procedures have been proposed. These are based on novel concepts which recognise that (1) most of these proteins follow a sequential distribution pattern in the brain suggesting a seeding mechanism and cell-to-cell propagation; (2) some of the neurodegeneration-associated proteins can be detected in peripheral organs; and (3) concomitant presence of neurodegeneration-associated proteins is more the rule than the exception. These concepts, together with the fact that the clinical symptoms do not unequivocally reflect the molecular pathological background, place the neuropathological examination at the centre of requirements for an accurate diagnosis. The need for quality control in biomarker development, clinical and neuroimaging studies, and evaluation of therapy trials, as well as an increasing demand for the general public to better understand human brain disorders, underlines the importance for a renaissance of postmortem neuropathological studies at this time. This review summarises recent advances in neuropathological diagnosis and reports novel aspects of relevance for general pathological practice.

Astrocytes contribute to the pathogenesis of neurodegenerative proteinopathies as influencing neuronal degeneration or neuroprotection, and also act as potential mediators of the propagation or elimination of disease-associated proteins. Protein astrogliopathies can be observed in different forms of neurodegenerative conditions. Morphological characterization of astrogliopathy is used only for the classification of tauopathies. Currently, at least six types of astrocytic tau pathologies are distinguished. Astrocytic plaques (AP), tufted astrocytes (TAs), ramified astrocytes (RA), and globular astroglial inclusions are seen predominantly in primary tauopathies, while thorn-shaped astrocytes (TSA) and granular/fuzzy astrocytes (GFA) are evaluated in aging-related tau astrogliopathy (ARTAG). ARTAG can be seen in the white and gray matter and subpial, subependymal, and perivascular locations. Some of these overlap with the features of tau pathology seen in Chronic traumatic encephalopathy (CTE). Furthermore, gray matter ARTAG shares features with primary tauopathy-related astrocytic tau pathology. Sequential distribution patterns have been described for tau astrogliopathies. Importantly, astrocytic tau pathology in primary tauopathies can be observed in brain areas without neuronal tau deposition. The various morphologies of tau astrogliopathy might reflect a role in the propagation of pathological tau protein, an early response to a yet unidentified neurodegeneration-inducing event, or, particularly for ARTAG, a response to a repeated or prolonged pathogenic process such as blood-brain barrier dysfunction or local mechanical impact. The concept of tau astrogliopathies and ARTAG facilitated communication among research disciplines and triggered the investigation of the significance of astrocytic lesions in neurodegenerative conditions.

Dark septate endophytes (DSE) are a form-group of root endophytic fungi with elusive functions. Here, the genomes of two common DSE of semiarid areas, Cadophora sp. and Periconia macrospinosa were sequenced and analyzed with another 32 ascomycetes of different lifestyles. Cadophora sp. (Helotiales) and P. macrospinosa (Pleosporales) have genomes of 70.46 Mb and 54.99 Mb with 22,766 and 18,750 gene models, respectively. The majority of DSE-specific protein clusters lack functional annotation with no similarity to characterized proteins, implying that they have evolved unique genetic innovations. Both DSE possess an expanded number of carbohydrate active enzymes (CAZymes), including plant cell wall degrading enzymes (PCWDEs). Those were similar in three other DSE, and contributed a signal for the separation of root endophytes in principal component analyses of CAZymes, indicating shared genomic traits of DSE fungi. Number of secreted proteases and lipases, aquaporins, and genes linked to melanin synthesis were also relatively high in our fungi. In spite of certain similarities between our two DSE, we observed low levels of convergence in their gene family evolution. This suggests that, despite originating from the same habitat, these two fungi evolved along different evolutionary trajectories and display considerable functional differences within the endophytic lifestyle.

Neurodegenerative diseases are a pathologically, clinically and genetically diverse group of disorders without effective disease-modifying therapies. Pathologically, these disorders are characterised by disease-specific protein aggregates in neurons and/or glia and referred to as proteinopathies. Many neurodegenerative diseases show pathological overlap with the same abnormally deposited protein occurring in anatomically distinct regions, which give rise to specific patterns of cognitive and motor clinical phenotypes. Sequential distribution patterns of protein inclusions throughout the brain have been described. Rather than occurring in isolation, it is increasingly recognised that combinations of one or more proteinopathies with or without cerebrovascular disease frequently occur in individuals with neurodegenerative diseases. In addition, complex constellations of ageing-related and incidental pathologies associated with tau, TDP-43, Aβ, α-synuclein deposition have been commonly reported in longitudinal ageing studies. This review provides an overview of current classification of neurodegenerative and age-related pathologies and presents the spectrum and complexity of mixed pathologies in community-based, longitudinal ageing studies, in major proteinopathies, and genetic conditions. Mixed pathologies are commonly reported in individuals >65 years with and without cognitive impairment; however, they are increasingly recognised in younger individuals (<65 years). Mixed pathologies are thought to lower the threshold for developing cognitive impairment and dementia. Hereditary neurodegenerative diseases also show a diverse range of mixed pathologies beyond the proteinopathy primarily linked to the genetic abnormality. Cases with mixed pathologies might show a different clinical course, which has prognostic relevance and obvious implications for biomarker and therapy development, and stratifying patients for clinical trials.

Iron accumulation in the brain is a common feature of many neurodegenerative diseases. Its involvement spans across the main proteinopathies involving tau, amyloid-beta, alpha-synuclein, and TDP-43. Accumulating evidence supports the contribution of iron in disease pathologies, but the delineation of its pathogenic role is yet challenged by the complex involvement of iron in multiple neurotoxicity mechanisms and evidence supporting a reciprocal influence between accumulation of iron and protein pathology. Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer’s disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer’s disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

Sporadic Creutzfeldt-Jakob disease is a fatal neurodegenerative disease caused by misfolded prion proteins (PrPSc). Effective therapeutics are currently not available and accurate diagnosis can be challenging. Clinical diagnostic criteria use a combination of characteristic neuropsychiatric symptoms, CSF proteins 14-3-3, MRI, and EEG. Supportive biomarkers, such as high CSF total tau, could aid the diagnostic process. However, discordant studies have led to controversies about the clinical value of some established surrogate biomarkers. Development and clinical application of disease-specific protein aggregation and amplification assays, such as real-time quaking induced conversion (RT-QuIC), have constituted major breakthroughs for the confident pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Updated criteria for the diagnosis of sporadic Creutzfeldt-Jakob disease, including application of RT-QuIC, should improve early clinical confirmation, surveillance, assessment of PrPSc seeding activity in different tissues, and trial monitoring. Moreover, emerging blood-based, prognostic, and potentially pre-symptomatic biomarker candidates are under investigation.

Tauopathies are classified according to whether tau deposits predominantly contain tau isoforms with three or four repeats of the microtubule-binding domain. Those in which four-repeat (4R) tau predominates are known as 4R-tauopathies, and include progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, globular glial tauopathies and conditions associated with specific MAPT mutations. In these diseases, 4R-tau deposits are found in various cell types and anatomical regions of the brain and the conditions share pathological, pathophysiological and clinical characteristics. Despite being considered ‘prototype’ tauopathies and, therefore, ideal for studying neuroprotective agents, 4R-tauopathies are still severe and untreatable diseases for which no validated biomarkers exist. However, advances in research have addressed the issues of phenotypic overlap, early clinical diagnosis, pathophysiology and identification of biomarkers, setting a road map towards development of treatments. New clinical criteria have been developed and large cohorts with early disease are being followed up in prospective studies. New clinical trial readouts are emerging and biomarker research is focused on molecular pathways that have been identified. Lessons learned from failed trials of neuroprotective drugs are being used to design new trials. In this Review, we present an overview of the latest research in 4R-tauopathies, with a focus on progressive supranuclear palsy, and discuss how current evidence dictates ongoing and future research goals.In this Review, Stamelou et al. present an overview of the latest research in 4-repeat tauopathies, with a focus on progressive supranuclear palsy, and discuss how current evidence dictates ongoing and future research goals.

Microglia play a crucial role in neurodegenerative diseases, but their specific involvement in disease progression remains unclear. Microglial diversity, initially described by Río-Hortega as varied morphological features, has been further explored through single-cell analyses identifying multiple subtypes. These findings suggest microglia exhibit diverse morphological and functional changes depending on pathological conditions even within the same disease. However, there is a paucity of data on progressive supranuclear palsy a (PSP), a tauopathy characterized by neuronal and glial tau pathologies. This study investigates the role of microglia in the frontal cortex of PSP. We performed immunohistochemistry for Iba1 and HLA-DR microglial markers in nine PSP cases and nine age-matched controls. Quantitative evaluation of positive regions in the cortex and white matter was conducted using HALO®. Morphological analysis of Iba1-positive cells was performed with the HALO Microglial Activation Module. The snRNA-seq on frozen samples from three PSP and three controls identified differentially expressed genes (DEGs) and GO enrichment. PSP-specific microglial subclusters were compared with previously reported subtypes (DAM, MgND, HAM). Iba1-positive microglia load is significantly increased only in the white matter in PSP, while HLA-DR-positive microglia load is increased in both the cortex and white matter. Microglia in PSP exhibited significantly longer processes, more branching, and larger cell bodies, particularly in the white matter. The snRNA-seq identified four PSP-specific subclusters, including those with high homeostatic gene expression (SC0), MHC class II pathway activation (SC0, 2, 4) and clusters enriched with aging-related genes (SC5). GO enrichment revealed functional diversity, including clusters enriched with aging-related genes. Modulation scoring did not reveal clear similarities with previously reported microglial subtype gene sets. This study reveals unique microglial morphological and functional characteristics in the PSP affected frontal cortex.