Journal of experimental neurology最新文献_第6页

Cathepsin D: A Candidate Link between Amyloid β-protein and Tauopathy in Alzheimer Disease. 组织蛋白酶D:淀粉样蛋白β-蛋白与阿尔茨海默病tau病变之间的候选联系。

Journal of experimental neurology Pub Date : 2021-01-01

Caitlin N Suire, Malcolm A Leissring

{"title":"Cathepsin D: A Candidate Link between Amyloid β-protein and Tauopathy in Alzheimer Disease.","authors":"Caitlin N Suire, Malcolm A Leissring","doi":"","DOIUrl":"","url":null,"abstract":"Alzheimer disease (AD) is a debilitating neurodegenerative disorder characterized by extracellular deposition of the amyloid β-protein (Aβ) and intraneuronal accumulation of the microtubule-associated protein, tau. Despite a wealth of experimental and genetic evidence implicating both Aβ and tau in the pathogenesis of AD, the precise molecular links between these two pathological hallmarks have remained surprisingly elusive. Here, we review emerging evidence for a critical nexus among Aβ, tau, and the lysosomal protease cathepsin D (CatD) that we hypothesize may play a pivotal role in the etiology of AD. CatD degrades both Aβ and tau in vitro, but the in vivo relevance of this lysosomal protease to these principally extracellular and cytosolic proteins, respectively, had remained undefined for many decades. Recently, however, our group found that genetic deletion of CatD in mice results in dramatic accumulation of Aβ in lysosomes, revealing that Aβ is normally trafficked to lysosomes in substantial quantities. Moreover, emerging evidence suggests that tau is also trafficked to the lysosome via chaperone-mediated autophagy and other trafficking pathways. Thus, Aβ, tau and CatD are colocalized in the lysosome, an organelle that shows dysfunction early in AD pathogenesis, where they can potentially interact. Notably, we discovered that Aβ42-the Aβ species most strongly linked to AD pathogenesis-is a highly potent, low-nanomolar, competitive inhibitor of CatD. Taking these observations together, we hypothesize that Aβ42 may trigger tauopathy by competitive inhibition of CatD-mediated degradation of tau-pathogenic forms of tau, in particular. Herein, we review the evidence supporting this hypothesis and explore the implications for the molecular pathogenesis of AD. Future research into these novel mechanistic links among Aβ, tau and CatD promises to expand our understanding of the etiology of AD and could potentially lead to novel therapeutic approaches for combatting this devastating disease of brain and mind.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":" ","pages":"10-15"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25432524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glutaminergic Signaling in the Nucleus Accumbens Modulates the Behavioral Response to Acute and Chronic Methylphenidate 伏隔核谷氨酰胺能信号调节对急性和慢性哌甲酯的行为反应

Journal of experimental neurology Pub Date : 2021-01-01 DOI: 10.33696/NEUROL.2.036

Nicholas King, Thomas Mink, N. Kharas, N. Dafny

{"title":"Glutaminergic Signaling in the Nucleus Accumbens Modulates the Behavioral Response to Acute and Chronic Methylphenidate","authors":"Nicholas King, Thomas Mink, N. Kharas, N. Dafny","doi":"10.33696/NEUROL.2.036","DOIUrl":"https://doi.org/10.33696/NEUROL.2.036","url":null,"abstract":"Methylphenidate (MPD) is a psychostimulant that acts on the CNS to produce behavioral effects. The nucleus accumbens (NAc) is involved in this, however the role of the NAc’s glutaminergic system in the behavioral response to MPD has not been studied. Three groups of animals were used: control, sham NAc lesions, and glutaminergic-specific (ibotenic acid toxin) NAc lesion groups. On experimental day (ED) 1, all groups received saline. On ED 2, NAc surgeries took place, followed by a 5-day recovery period (ED 3-7). On ED 8 a post-surgical baseline recording was obtained. Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14) to produce a chronic effect of MPD exposure, behavioral sensitization, then three days of washout (ED 15-17), followed by a re-challenge with 2.5 mg/ kg MPD on ED 18. Locomotive activity was recorded for 60 minutes after each injection. All groups showed an increase in behavioral activity following acute MPD exposure, and developed behavioral sensitization following chronic MPD exposure that was maintained after washout. Compared to NAc intact controls and sham lesions, glutaminergic selective ibotenic acid lesions to the NAc significantly (P<0.05) attenuated the horizontal activity response to both acute and chronic MPD. Glutaminergic selective ibotenic acid lesions to the NAc also resulted in further significant (P<0.05) augmentation of stereotypic activity above the control group. The glutaminergic lesion failed to modulate total distance traveled. This indicates that glutaminergic signaling in the NAc modulates behavioral activity circuits in the NAc differently, and suggests a role in the volitional response to MPD.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69670511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Combined Antiseizure Efficacy of Cannabidiol and Clonazepam in a Conditional Mouse Model of Dravet Syndrome. 大麻二酚和氯硝西泮联合抗惊厥对条件性小鼠Dravet综合征的影响。

Journal of experimental neurology Pub Date : 2021-01-01 DOI: 10.33696/neurol.2.040

Shu-Hui Chuang, Ruth E Westenbroek, Nephi Stella, William A Catterall

{"title":"Combined Antiseizure Efficacy of Cannabidiol and Clonazepam in a Conditional Mouse Model of Dravet Syndrome.","authors":"Shu-Hui Chuang, Ruth E Westenbroek, Nephi Stella, William A Catterall","doi":"10.33696/neurol.2.040","DOIUrl":"https://doi.org/10.33696/neurol.2.040","url":null,"abstract":"Dravet Syndrome (DS) is a severe childhood epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene encoding brain type-I voltage-gated sodium channel Nav1.1. DS is a devastating disease that typically begins at six to nine months of age. Symptoms include recurrent intractable seizures and premature death with severe neuropsychiatric comorbidities, including hyperactivity, sleep disorder, anxiety-like behaviors, impaired social interactions, and cognitive deficits. There is an urgent unmet need for therapeutic approaches that control and cure DS, as available therapeutic interventions have poor efficacy, intolerance, or other side effects. Here we investigated the therapeutic potential of combining the benzodiazepine clonazepam (CLZ) with the nonpsychotropic phytocannabinoid cannabidiol (CBD) against thermally induced febrile seizures in a conditional mouse model of DS. Our results show that a low dose of CLZ alone or combined with CBD elevated the threshold temperature for the thermal induction of seizures. Combination of CLZ with CBD significantly reduced seizure duration compared to the vehicle or CLZ alone, but did not affect seizure severity, indicating potential additive actions of CLZ and CBD on the duration of seizures. Our findings provide preclinical evidence supporting combination therapy of CLZ and CBD for treatment of febrile seizures in DS.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":"2 2","pages":"81-85"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39223203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 5

The Spread of Spectrin in Ataxia and Neurodegenerative Disease. 幽灵蛋白在共济失调和神经退行性疾病中的传播。

Journal of experimental neurology Pub Date : 2021-01-01

Jon S Morrow, Michael C Stankewich

{"title":"The Spread of Spectrin in Ataxia and Neurodegenerative Disease.","authors":"Jon S Morrow, Michael C Stankewich","doi":"","DOIUrl":"","url":null,"abstract":"Experimental and hereditary defects in the ubiquitous scaffolding proteins of the spectrin gene family cause an array of neuropathologies. Most recognized are ataxias caused by missense, deletions, or truncations in the SPTBN2 gene that encodes beta III spectrin. Such mutations disrupt the organization of post-synaptic receptors, their active transport through the secretory pathway, and the organization and dynamics of the actin-based neuronal skeleton. Similar mutations in SPTAN1 that encodes alpha II spectrin cause severe and usually lethal neurodevelopmental defects including one form of early infantile epileptic encephalopathy type 5 (West syndrome). Defects in these and other spectrins are implicated in degenerative and psychiatric conditions. In recent published work, we describe in mice a novel variant of alpha II spectrin that results in a progressive ataxia with widespread neurodegenerative change. The action of this variant is distinct, in that rather than disrupting a constitutive ligand-binding function of spectrin, the mutation alters its response to calcium and calmodulin-regulated signaling pathways including its response to calpain activation. As such, it represents a novel spectrinopathy that targets a key regulatory pathway where calcium and tyrosine kinase signals converge. Here we briefly discuss the various roles of spectrin in neuronal processes and calcium activated regulatory inputs that control its participation in neuronal growth, organization, and remodeling. We hypothesize that damage to the neuronal spectrin scaffold may be a common final pathway in many neurodegenerative disorders. Targeting the pathways that regulate spectrin function may thus offer novel avenues for therapeutic intervention.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":"2 3","pages":"131-139"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39423195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential Fecal Microbiome Dysbiosis after Equivalent Traumatic Brain Injury in Aged Versus Young Adult Mice. 老年和年轻成年小鼠等效创伤性脑损伤后粪便微生物组的差异性失调。

Journal of experimental neurology Pub Date : 2021-01-01 DOI: 10.33696/neurol.2.044

Booker T Davis, Mecca B A R Islam, Promi Das, Jack A Gilbert, Karen J Ho, Steven J Schwulst

{"title":"Differential Fecal Microbiome Dysbiosis after Equivalent Traumatic Brain Injury in Aged Versus Young Adult Mice.","authors":"Booker T Davis, Mecca B A R Islam, Promi Das, Jack A Gilbert, Karen J Ho, Steven J Schwulst","doi":"10.33696/neurol.2.044","DOIUrl":"10.33696/neurol.2.044","url":null,"abstract":"Traumatic brain injury (TBI) has a bimodal age distribution with peak incidence at age 24 and age 65 with worse outcomes developing in aged populations. Few studies have specifically addressed age at the time of injury as an independent biologic variable in TBI-associated secondary pathology. Within the framework of our published work, identifying age related effects of TBI on neuropathology, cognition, memory and motor function we analyzed fecal pellets collected from young and aged TBI animals to assess for age-induced effects in TBI induced dysbiosis. In this follow up, work we hypothesized increased dysbiosis after TBI in aged (80-week-old, N=10) versus young (14-week-old, N=10) mice. C57BL/6 males received a sham incision or TBI via open-head controlled cortical impact. Fresh stool pellets were collected 1-day pre-TBI, then 1, 7, and 28-days post-TBI for 16S rRNA gene sequencing and taxonomic analysis. Data revealed an age induced increase in disease associated microbial species which were exacerbated by injury. Consistent with our hypothesis, aged mice demonstrated a high number of disease associated changes to the gut microbiome pre- and post-injury. Our data suggest divergent microbiome phenotypes in injury between young and aged reflecting a previously unknown interaction between age, TBI, and the gut-brain axis implying the need for different treatment strategies.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":"2 3","pages":"120-130"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8612634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39660057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Capillary Stalling: A Mechanism of Decreased Cerebral Blood Flow in AD/ADRD. 毛细血管停滞：AD/ADRD脑血流量减少的机制。

Journal of experimental neurology Pub Date : 2021-01-01 DOI: 10.33696/neurol.2.048

Reece Crumpler, Richard J Roman, Fan Fan

{"title":"Capillary Stalling: A Mechanism of Decreased Cerebral Blood Flow in AD/ADRD.","authors":"Reece Crumpler, Richard J Roman, Fan Fan","doi":"10.33696/neurol.2.048","DOIUrl":"10.33696/neurol.2.048","url":null,"abstract":"Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are debilitating conditions that are highly associated with aging populations, especially those with comorbidities such as diabetes and hypertension. In addition to the classical pathological findings of AD, such as beta-amyloid (Aβ) accumulation and tau hyperphosphorylation, vascular dysfunction is also associated with the progression of the disease. Vascular dysfunction in AD is associated with decreased cerebral blood flow (CBF). Impaired CBF is an early and persistent symptom of AD/ADRD and is thought to be associated with deficient autoregulation and neurovascular coupling. Another recently elucidated mechanism that contributes to cerebral hypoperfusion is capillary stalling, or the temporary arrest of capillary blood flow usually precipitated by a stalled leukocyte or constriction of actin-containing capillary pericytes. Stalled capillaries are associated with decreased CBF and impaired cognitive performance. AD/ADRD are associated with chronic, low-level inflammation, which contributes to capillary stalling by increased cell adhesion molecules, circulating leukocytes, and reactive oxygen species production. Recent research has shed light on potential targets to decrease capillary stalling in AD mice. Separate inhibition of Ly6G and VEGF-A has been shown to decrease capillary stalling and increase CBF in AD mice. These results suggest that targeting stalled capillaries could influence the outcome of AD and potentially be a target for future therapies.","PeriodicalId":73744,"journal":{"name":"Journal of experimental neurology","volume":"2 4","pages":"149-153"},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8754422/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39910127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Retroviral Elements in Human Evolution and Neural Development. 逆转录病毒在人类进化和神经发育中的作用。

Journal of experimental neurology Pub Date : 2021-01-01

Tongguang Wang, Tara T Doucet-O'Hare, Lisa Henderson, Rachel P M Abrams, Avindra Nath

引用次数: 0

Targeting the Cancer Stem Cell (CSC) Phenotype: Uprooting the Evil Seed 靶向癌症干细胞(CSC)表型:根除邪恶的种子

Journal of experimental neurology Pub Date : 2020-12-31 DOI: 10.33696/NEUROL.1.027

H. Lopez-Bertoni, J. Laterra

引用次数: 0

Alzheimer and It’s Possible Therapy: A Review 阿尔茨海默病及其可能的治疗方法综述

Journal of experimental neurology Pub Date : 2020-12-31 DOI: 10.33696/NEUROL.1.019

A. Chakraborty, Anil Diwan

引用次数: 1

Cutaneous Side Effects of First-Second Line Oral Disease - Modifying Treatments in Patients with Multiple Sclero 多发性硬化症患者一二线口腔疾病的皮肤副作用-改良治疗

Journal of experimental neurology Pub Date : 2020-12-31 DOI: 10.33696/NEUROL.1.024

Doruk Arslan, A. Tuncer

引用次数: 0