Molecular and cellular neurosciences
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Mol. Cell. Neurosci. · Jul 2021
Elevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease.
Down syndrome (DS) is caused by trisomy of chromosome 21, which leads to a propensity to develop amyloid β (Aβ) brain pathology in early adulthood followed later by cognitive and behavioral deterioration. Characterization of the Aβ pathology is important to better understand the clinical deterioration of DS individuals and to identify interventive strategies. Brain samples from people with DS and Alzheimer's disease (AD), as well as non-demented controls (NDC), were analyzed with respect to different Aβ species. ⋯ Elevated levels of soluble Aβ protofibrils and insoluble Aβx-40 and Aβx-42 in formic acid brain extracts, and elevated immunohistochemical staining of Aβ deposits were demonstrated with the antibody BAN2401 (lecanemab) in DS and AD compared with NDC. These data and the promising data in a large phase 2 CE clinical trial with lecanemab suggest that lecanemab may have the potential to preserve cognitive capacity in DS. Lecanemab is currently in a phase 3 CE clinical trial.
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Mol. Cell. Neurosci. · Jun 2019
ReviewFluid and PET biomarkers for amyloid pathology in Alzheimer's disease.
Alzheimer's disease (AD) is characterized by amyloid plaques and tau pathology (neurofibrillary tangles and neuropil threads). Amyloid plaques are primarily composed of aggregated and oligomeric β-amyloid (Aβ) peptides ending at position 42 (Aβ42). ⋯ Therefore, sensitive, specific and robust biomarkers to identify brain amyloidosis are central in AD research. Here, we discuss fluid and PET biomarkers for Aβ and their application.
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The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. ⋯ Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.
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Mol. Cell. Neurosci. · Jan 2019
A new function for Prokineticin 2: Recruitment of SVZ-derived neuroblasts to the injured cortex in a mouse model of traumatic brain injury.
Traumatic brain injury is an important cause of global morbidity and mortality. After an initial injury, there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim to both counteract these mechanisms and replenish the lost cell population in order to improve recovery. ⋯ We then show that administration of a PROK2 receptor antagonist decreases the number of SVZ cells that reach the injured cortex, while injection of recombinant PROK2 into the cortex of uninjured mice attracts SVZ cells. We also demonstrate that cells expressing PROK2 in vitro directionally attract SVZ cells. These data suggest that PROK2 could be utilized in regeneration efforts for the acutely injured mammalian cortex.
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Mol. Cell. Neurosci. · Apr 2018
24S-hydroxycholesterol suppresses neuromuscular transmission in SOD1(G93A) mice: A possible role of NO and lipid rafts.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the initial denervation of skeletal muscle and subsequent death of motor neurons. A dying-back pattern of ALS suggests a crucial role for neuromuscular junction dysfunction. In the present study, microelectrode recording of postsynaptic currents and optical detection of synaptic vesicle traffic (FM1-43 dye) and intracellular NO levels (DAF-FM DA) were used to examine the effect of the major brain-derived cholesterol metabolite 24S-hydroxycholesterol (24S-HC, 0.4 μM) on neuromuscular transmission in the diaphragm of transgenic mice carrying a mutant superoxide dismutase 1 (SODG93A). ⋯ Of note, 24S-HC enhanced the labeling of synaptic membranes with B-subunit of cholera toxin, suggesting an increase in lipid ordering. Lipid raft-disrupting agents (methyl-β-cyclodextrin, sphingomyelinase) prevented the action of 24S-HC on both lipid raft marker labeling and NO synthesis. Together, these experiments indicate that 24S-HC is able to suppress the exocytotic release of neurotransmitter in response to intense activity via a NO/lipid raft-dependent pathway in the neuromuscular junctions of SODG93A mice.