Abstract:
:Mutations in APP (amyloid precursor protein), PSEN1 (presenilin 1) or PSEN2 (presenilin 2) are the main cause of early-onset familial forms of Alzheimer's disease (autosomal dominant AD or ADAD). These genes affect γ-secretase-dependent generation of Amyloid β (Aβ) peptides, the main constituent of amyloid plaques and one of the pathological hallmarks of AD. Evaluation of patients with ADAD includes assessment of family history, clinical presentation, biomarkers, neuropathology when available and DNA sequencing data. These analyses frequently uncover novel variants of unknown significance in ADAD genes. This presents a barrier to recruitment of such individuals into clinical trials, unless a biochemical test can demonstrate that a novel mutation results in altered APP processing in a manner consistent with pathogenicity. Here we describe generation and characterization of a novel presenilin 1 and 2 double knock-out in N2A mouse neuroblastoma cells using CRISPR/Cas9, which results in complete ablation of Aβ production, decreased Pen-2 expression and Nicastrin glycosylation. Because of the absence of background Aβ secretion from endogenous γ-secretases, these cells can be used for validation of PSEN1 and PSEN2 variant effects on production of Aβ or other γ-secretase substrates and for biochemical studies of γ-secretase function using novel variants. We examined several PSEN1 and PSEN2 mutations of known and unknown pathogenicity. Known mutants increased Aβ42/Aβ40 ratio with varying effect on Aβ40, Aβ42, total Aβ levels and Pen-2 expression, which aligns with previous work on these mutants. Our data on novel PSEN1 V142F, G206V and G206D mutations suggest that these mutations underlie the reported clinical observations in ADAD patients. We believe our novel cell line will be valuable for the scientific community for reliable validation of presenilin mutations and helpful in defining their pathogenicity to improve and facilitate evaluation of ADAD patients, particularly in the context of enrollment in clinical trials.
journal_name
Neurobiol Disjournal_title
Neurobiology of diseaseauthors
Pimenova AA,Goate AMdoi
10.1016/j.nbd.2020.104785subject
Has Abstractpub_date
2020-05-01 00:00:00pages
104785eissn
0969-9961issn
1095-953Xpii
S0969-9961(20)30060-7journal_volume
138pub_type
杂志文章abstract::The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and ma...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2010.02.005
更新日期:2010-07-01 00:00:00
abstract:AIM:Recent studies revealed that pharmacological modulation of NAE-hydrolyzing acid amidase (NAAA) can be achieved with PEA oxazoline (PEA-OXA). Hence, the aim of the present work was to thoroughly evaluate the anti-inflammatory and neuroprotective effects of PEA-OXA in an experimental model of vascular dementia (VaD) ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2019.01.007
更新日期:2019-05-01 00:00:00
abstract::Markers of the kynurenine pathway were studied in postmortem frontal cortex obtained from individuals with schizophrenia and controls. Quantitative endpoint RT-PCR was used to measure mRNA transcripts. Of the two enzymes capable of catalyzing the first step in the pathway, tryptophan 2,3-dioxygenase (TDO2) and indolea...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2003.12.015
更新日期:2004-04-01 00:00:00
abstract::In Alzheimer's disease (AD), the cognitive reserve theory predicts that at any level of assessed clinical severity, the underlying brain pathology is more advanced in patients with more cognitive reserve. Recent evidences suggest that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We inves...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2010.07.007
更新日期:2010-11-01 00:00:00
abstract::Recent studies indicate that the Parkinson's disease-linked leucine-rich repeat kinase 2 (LRRK2) modulates cytoskeletal functions by regulating actin and tubulin dynamics, thereby affecting neurite outgrowth. By interactome analysis we demonstrate that the binding of LRRK2 to tubulins is significantly enhanced by phar...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2012.12.019
更新日期:2013-06-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by the progressive loss of motor neurons, leading to profound weakness and eventual death of affected individuals. For the vast majority of patients with ALS, the etiology of the disorder is unknown, and although multiple clinical...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1006/nbdi.1999.0266
更新日期:1999-10-01 00:00:00
abstract::The protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygous for the homeodomai...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2015.05.015
更新日期:2015-10-01 00:00:00
abstract::The deposition and accumulation of amyloid-beta-peptide (Abeta) in the brain are considered a sine qua non for Alzheimer's disease. The experimental delivery of fibrilized Abeta serves as a cellular model for several facets of the disease including the induction of synaptic dysfunction and apoptosis. c-Abl kinase is i...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2004.06.007
更新日期:2004-11-01 00:00:00
abstract::Following intracerebral inoculation, the BeAn 8386 strain of Theiler's virus causes persistent infection and inflammatory demyelinating encephalomyelitis in the spinal cord of T-cell defective SJL/J mice, which is widely used as a model of multiple sclerosis. In contrast, C57BL/6 (B6) mice clear the virus and develop ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2016.12.020
更新日期:2017-03-01 00:00:00
abstract::Recently an aspartyl protease with beta-secretase activity called BACE was identified. In the present paper we showed that BACE is modulated by the oxidative stress product 4-hydroxynonenal (HNE). Exposure of NT(2) neurons to the two classical pro-oxidant stimuli ascorbate/FeSO(4) and H(2)O(2)/FeSO(4) resulted in a si...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1006/nbdi.2002.0515
更新日期:2002-08-01 00:00:00
abstract::Charcot-Marie-Tooth disease is a commonly inherited form of neuropathy. Although named over 100 years ago, identification of subtypes of Charcot-Marie-Tooth has rapidly expanded in the preceding decades with the advancement of genetic sequencing, including type 2F (CMT2F), due to mutations in heat shock protein 27 (Hs...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2019.104505
更新日期:2019-10-01 00:00:00
abstract::Genetic and biochemical abnormalities associated with alpha-synuclein are implicated in the etiology of Parkinson's disease (PD). In this study, altered locomotor behavior linked to the expression of mutant or wildtype human alpha-synuclein was investigated. A53T alpha-synuclein transgenic (A53T-tg) mice exhibited nor...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2005.08.005
更新日期:2006-02-01 00:00:00
abstract::Microglia and macrophages express the alpha(M)/beta(2) integrin complement-receptor-3 (CR3/MAC-1; CD11b/CD18) and scavenger-receptor-AI/II (SRAI/II). Both can mediate myelin phagocytosis. We document that CR3/MAC-1 mediated myelin phagocytosis in microglia is modulated by complement and anti-CR3/MAC-1 mAbs. Complement...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/s0969-9961(02)00008-6
更新日期:2003-02-01 00:00:00
abstract::Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1006/nbdi.2000.0373
更新日期:2001-04-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. Although 10% of ALS cases are familial (FALS), the majority are sporadic (SALS) and probably associated to a multifactorial etiology. Currently ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2014.12.002
更新日期:2015-02-01 00:00:00
abstract::Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the major animal model for DS, have severe cognitive and synaptic plasticity dysfunctions caused by excessive inhibition in their temporal lobe structures. Here we employed a multid...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.11.010
更新日期:2014-03-01 00:00:00
abstract::The most appropriate time for the initiation of dopaminergic symptomatic therapy in Parkinson's disease remains debatable. It has been suggested that early correction of basal ganglia pathophysiological abnormalities may have long-term beneficial effects. To test this hypothesis, we investigated the early and delayed ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.12.009
更新日期:2014-04-01 00:00:00
abstract::Using an in vitro translation assay to screen a human brain cDNA library, we isolated the microtubule-associated protein Tau and determined it to be a caspase-3 substrate whose C-terminal cleavage occurred during neuronal apoptosis. DeltaTau, the 50-kDa cleavage product, was detected by Western blot in apoptotic corti...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1006/nbdi.2000.0335
更新日期:2001-02-01 00:00:00
abstract::Alzheimer's disease (AD) is the most common dementia worldwide and is characterized by the presence of senile plaques by amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated Tau protein. These changes lead to progressive neuronal degeneration and dysfunction, resulting in severe brain atrophy and cogni...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2020.105219
更新日期:2021-01-01 00:00:00
abstract::Transglutaminase 2 (TG2) is a multifunctional protein that modulates cell survival and death pathways. It is upregulated in numerous ischemic models, and protects primary neurons from oxygen and glucose deprivation. TG2 binds to the hypoxia inducible factor (HIF) 1beta and decreases the upregulation of hypoxic-induced...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2010.04.018
更新日期:2010-09-01 00:00:00
abstract::Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession o...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2020.105175
更新日期:2021-01-01 00:00:00
abstract::Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 gene mutation in vascular smooth muscle cells (VSMCs), leading to ischemic stroke and vascular dementia. To date, the pathogenesis of CADASIL remains poorly understo...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2019.104561
更新日期:2019-12-01 00:00:00
abstract::Beta power suppression in the basal ganglia is stronger during movements that require high force levels and high movement effort but it has been difficult to dissociate the two. We recorded scalp EEG and basal ganglia local field potentials in Parkinson's disease patients (11 STN, 7 GPi) ON and OFF dopaminergic medica...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2019.03.004
更新日期:2019-07-01 00:00:00
abstract::It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alz...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2017.03.011
更新日期:2018-01-01 00:00:00
abstract::Lyme disease, caused by the bacterium Borrelia burgdorferi, can cause multi-systemic signs and symptoms, including peripheral and central nervous system disease. This review examines the evidence for and mechanisms of inflammation in neurologic Lyme disease, with a specific focus on the central nervous system, drawing...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2009.11.016
更新日期:2010-03-01 00:00:00
abstract::Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-d-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and N...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2011.12.051
更新日期:2012-04-01 00:00:00
abstract::We have explored the molecular mechanism underlying amyloid beta-peptide (Abeta)-mediated cytotoxicity in vitro. Exposure of murine cerebral endothelial cells (CECs) or C6 glioma cells to Abeta25-35 resulted in dose-dependent cell death. Ceramide is a pro-apoptotic lipid mediator. Forced elevation of cellular ceramide...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2004.06.001
更新日期:2004-10-01 00:00:00
abstract::The aim of the present study is to better understand oxygen-sensitive adaptative pathways underlying the hypoxic preconditioning-induced protection of the brain against ischemia. Using oligonucleotide microarrays, we examined the brain genomic response of adult mice following hypoxia preconditioning (8% O2 for 1 or 6 ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2005.06.002
更新日期:2006-01-01 00:00:00
abstract::Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a dynamic GAA repeat expansion mutation within intron 1 of the FXN gene. Studies of mouse models for other trinucleotide repeat (TNR) disorders have revealed an important role of mismatch repair (MMR) proteins in TNR instability. T...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2012.01.002
更新日期:2012-04-01 00:00:00
abstract::Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.08.003
更新日期:2013-11-01 00:00:00