Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.

Tauopathies are neurodegenerative diseases that typically require postmortem examination for a definitive diagnosis. Detecting neurotoxic tau fragments in cerebrospinal fluid (CSF) and serum provides an opportunity for in vivo diagnosis and disease monitoring. Current assays primarily focus on total tau or phospho-tau, overlooking other post-translational modifications (PTMs). Caspase-cleaved tau is a significant component of AD neuropathological lesions, and experimental studies confirm the high neurotoxicity of these tau species. Recent evidence indicates that certain caspase-cleaved tau species, such as D13 and D402, are abundant in AD brain neurons and only show a modest degree of co-occurrence with phospho-tau, meaning caspase-truncated tau pathology is partially distinct and complementary to phospho-tau pathology. Furthermore, these caspase-cleaved tau species are nearly absent in 4-repeat tauopathies. In this review, we will discuss the significance of caspase-cleaved tau in the development of tauopathies, specifically emphasizing its role in AD. In addition, we will explore the potential of caspase-cleaved tau as a biomarker and the advantages for drug development targeting caspase-6. Developing specific and sensitive assays for caspase-cleaved tau in biofluids holds promise for improving the diagnosis and monitoring of tauopathies, providing valuable insights into disease progression and treatment efficacy.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

The role of co-neurotransmitters in sleep and wake regulation.

Sleep and wakefulness control in the mammalian brain requires the coordination of various discrete interconnected neurons. According to the most conventional sleep model, wake-promoting neurons (WPNs) and sleep-promoting neurons (SPNs) compete for network dominance, creating a systematic "switch" that results in either the sleep or awake state. WPNs and SPNs are ubiquitous in the brainstem and diencephalon, areas that together contain <1% of the neurons in the human brain. Interestingly, many of these WPNs and SPNs co-express and co-release various types of the neurotransmitters that often have opposing modulatory effects on the network. Co-transmission is often beneficial to structures with limited numbers of neurons because it provides increasing computational capability and flexibility. Moreover, co-transmission allows subcortical structures to bi-directionally control postsynaptic neurons, thus helping to orchestrate several complex physiological functions such as sleep. Here, we present an in-depth review of co-transmission in hypothalamic WPNs and SPNs and discuss its functional significance in the sleep-wake network.

Subcortical neurodegeneration in chorea: Similarities and differences between chorea-acanthocytosis and Huntington's disease.

INTRODUCTION: Chorea-acanthocytosis (ChAc) and Huntington's disease (HD) are neurodegenerative conditions that share clinical and neuropathological features, despite their distinct genetic etiologies. METHODS: In order to compare these neuropathologies, serial gallocyanin-stained brain sections from three subjects with ChAc were analyzed and compared with our previous studies of eight HD cases, in addition to three hemispheres from two male controls. RESULTS: Astrogliosis was much greater in the ChAc striatum, as compared to that found in HD, with dramatic increase in total striatal glia numbers and the number of glia per striatal neuron. Striatal astrocytes are most likely derived from the striatal subependymal layer in ChAc, which showed massive proliferation. The thalamic centromedian-parafascicular complex is reciprocally connected to the striatum and is more heavily affected in HD than in ChAc. CONCLUSION: The distinct patterns of selective vulnerability and gliosis observed in HD and ChAc challenge simplistic views on the pathogenesis of these two diseases with rather similar clinical signs. The particular roles played by astroglia in ChAc and in HD clearly need to be elucidated in more detail.