Molecular Neurodegeneration

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels...

BACKGROUND: Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain...

No abstract text is available yet for this article.

No abstract text is available yet for this article.

BACKGROUND: Amyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer's disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates. METHOD: We used a multiplex antibody-based suspension bead array to measure the levels of 49 proteins in CSF from the Swedish GEDOC memory clinic cohort at the Karolinska University Hospital...

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. METHODS: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions...

BACKGROUND: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. METHODS: To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones...

BACKGROUND: Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer's, Parkinson's, and Huntington's disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions...

The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing broad capacity for adaptation and remodeling in response to stress that otherwise would challenge equilibrium between neuronal, glial, and vascular elements...

BACKGROUND: Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results...

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery...

Parkinson's Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson's Disease (PD) cases and 14 Controls...

BACKGROUND: Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants...

Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process...

Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm disorders. The circadian rhythm, a recurring 24-hour cycle governing human biological activity, is regulated by the hypothalamic suprachiasmatic nucleus (SCN) and endogenous transcriptional-translational feedback loops. Surprisingly, little attention has been given to investigating tauopathy-driven neuropathology in the SCN and the repercussions of SCN and circadian gene dysfunction in the human brain affected by tauopathies...

BACKGROUND: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181 , p-tau217 and p-tau231 with established immunoassay techniques. METHODS: We measured p-tau181 , p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods...

No abstract text is available yet for this article.

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p...

Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.