Sexual dimorphism of G protein-coupled receptor signaling in the brain

G protein-coupled receptors(GPCRs)represent the most substantial family of membrane receptors that are targeted by U.S.Food and Drug Administration-approved drugs.Much of the preclinical research to understand the pharmacology of many membrane receptors including GPCRs is derived from studies in male animal models(Karp and Reavey,2019).

Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing

The common marmoset(Callithrix jacchus)has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies.Epileptic marmosets have been independently reported in two Asian primate research centers.Nevertheless,the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated.Here,we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing.We identified 14558184 single nucleotide polymorphisms(SNPs)from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples.Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers.In addition,SNP and copy number variation(CNV)analyses suggested that the WW domain-containing oxidoreductase(WWOX)and Tyrosine-protein phosphatase nonreceptor type 21(PTPN21)genes may be associated with epilepsy in marmosets.Notably,KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets.This study provides valuable population genomic resources for marmosets in two Asian primate centers.Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers,while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.

Therapeutic potential of exercise-hormone irisin in Alzheimer's disease

Irisin is a myokine that is generated by cleavage of the membrane protein fibronectin type Ⅲ domain-containing protein 5(FNDC5) in response to physical exercise. Studies reveal that irisin/FNDC5 has neuroprotective functions against Alzheimer's disease, the most common form of dementia in the elderly, by improving cognitive function and reducing amyloid-β and tau pathologies as well as neuroinflammation in cell culture or animal models of Alzheimer's disease. Although current and ongoing studies on irisin/FNDC5 show promising results, further mechanistic studies are required to clarify its potential as a meaningful therapeutic target for alleviating Alzheimer's disease. We recently found that irisin treatment reduces amyloid-β pathology by increasing the activity/levels of amyloid-β-degrading enzyme neprilysin secreted from astrocytes. Herein, we present an overview of irisin/FNDC5's protective roles and mechanisms against Alzheimer's disease.

Iron regulatory protein 1: the deadly switch of ferroptosis

Ferroptosis,an iron-dependent cell death:Ferroptosis is a type of regulated necrosis,characterized by redox-active iron accumulation and increased free radical production derived by Fenton chemistry,that triggers oxidation of polyunsaturated fatty acids in phospholipids,loss of cellular membranes integrity,and leakage of intracellular contents.

Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease

The high metabolic demands of the brain require an efficient vascular system to be coupled with neural activity to supply adequate nutrients and oxygen.This supply is coordinated by the action of neurons,glial and vascular cells,known collectively as the neurovascular unit,which temporally and spatially regulate local cerebral blood flow through a process known as neurovascular coupling.In many neurodegenerative diseases,changes in functions of the neurovascular unit not only impair neurovascular coupling but also permeability of the blood-brain barrier,cerebral blood flow and clearance of waste from the brain.In order to study disease mechanisms,we need improved physiologicallyrelevant human models of the neurovascular unit.Advances towards modeling the cellular complexity of the neurovascular unit in vitro have been made using stem-cell derived organoids and more recently,vascularized organoids,enabling intricate studies of non-cell autonomous processes.Engineering and design innovations in microfluidic devices and tissue engineering are progressing our ability to interrogate the cerebrovasculature.These advanced models are being used to gain a better understanding of neurodegenerative disease processes and potential therapeutics.Continued innovation is required to build more physiologically-relevant models of the neurovascular unit encompassing both the cellular complexity and designed features to interrogate neurovascular unit functionality.

Commentary on"PANoptosis-like cell death in ischemia/reperfusion injury of retinal neurons"

See related article,pp 357-363Several decades have passed since programmedcell death(PCD)was identified.Apoptosis was first defined by Kerr in 1972,and later described by the Nobel Prices in Physiology or Medicine 2002,Sydney Brenner,John Sulston and Robert Horwitz,who defined genetic regulators of apoptosis(Diamantis et al.,2008).However,it was in 1858 when the German pathologist and biologist Rudolf Virchow identified for the first time the phenomenon of apoptosis,which he named necrobiosis,arguing that this form of cell death was completely different from the uncontrolled necrosis,suggesting the existence of two different types of cell death.Today,the knowledge in the field of cell death regulation is extensive,but still under continuous expansion.

Cerebral ischemia and neuroregeneration

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke （a form of cerebral ischemia）-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics （i.e., tissue plasminogen activator） and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies again st stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism（s） underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies （i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells） as it relates to cerebral ischemia.

海马前后部代谢的不均匀性:三维多体素~1H-MRS——初期结果

目的通过质子磁共振波谱成像定量检测健康年轻及年老受试者海马横断面前后方的代谢物浓度。材料和方法本前瞻性研究遵守美国健康保险携带和责任条例。

New insights on the molecular mechanisms of collateral sprouting after peripheral nerve injury

Axonal regeneration after injuries to the nervous system has been extensively studied due to its implication in motor and sensory functional recovery. Distinct types of regeneration has been identified, such as canonical axonal regeneration, defined as the growth of axons from the transected axonal stump to reinnervate the original target, or regenerative sprouting, in which the growth occurs from a region of the damaged axon either close or far from the injury site(Tuszynski and Steward, 2012).

Bursting the unfolded protein response accelerates axonal regeneration

Peripheral neuropathies refer to a group of conditions in which the peripheral nervous system(PNS)is damaged.These pathological state are are associated with weakness,pain,and loss of motor and sensory control.More than 100 types of peripheral neuropathies have been identified,with distinct symptoms and prognosis classified according to the type of damage to the nerves.Injury to peripheral nerves results in disabling loss of sensory and motor func-

情感淡漠卒中患者的前额叶N-乙酰天冬氨酸含量减少

Background: Although substantial numbers of stroke patients suffer from apathy, its causes are still poorly understood. Previous studies suggest that dysfunction of the frontal lobes is implicated in the pathophysiology of motivation. Our aim was to investigate the association between proton magnetic resonance spectr oscopy (H1-MRS) measurements in unaffected frontal lobes and apathy in a group of first-time stroke patients. Methods: 31 patients with a first-time ischemic stroke located outside the frontal lobes and 20 healthy subjects were included in the study. The authors performed single voxel H1-MRS in order to measure the N-acetylaspartate/creatine (NAA)/Cr, glutamate +glutamine (Glx)/Cr, choline ( Cho)/Cr and myo-inositol (mI)/Cr ratios in the frontal lobes. Patients were ass essed between days 7 and 12 post stroke. Diagnosis of apathy was made on the bas is of clinical observation, interview and Apathy Scale. Results: 13 out of 31 patients (42%) demonstrated apathy. Patie nts with apathy had lower NAA/Cr ratios in the right frontal lobe than non-apat hetic subjects. The patient group was divided into two subgroups: Those with lef t hemisphere strokes, and those with right hemisphere strokes. Of these subjects , significantly lowered NAA/Cr ratios were found in the right hemispheres of apa thetic patients in the subgroup with left-sided brain lesions. Conclusions: The se findings point to the association between apathy and frontal lobe integrity, suggest different reactions of the hemispheres and indicate that changes in the NAA/Cr ratio are related to the apathy.

Development of a potential PET probe for HDAC6 imaging in Alzheimer's disease

Although the epigenetic regulatory protein histone deacetylase 6(HDAC6)has been recently implicated in the etiology of Alzheimer’s disease(AD),little is known about the role of HDAC6 in the etiopathogenesis of AD and whether HDAC6 can be a potential therapeutic target for AD.Here,we performed positron emission tomography(PET)imaging in combination with histopathological analysis to better understand the underlying pathomechanisms of HDAC6 in AD.We first developed[^(18)F]PB118 which was demonstrated as a valid HDAC6 radioligand with excellent brain penetration and high specificity to HDAC6.PET studies of[^(18)F]PB118 in 5xFAD mice showed significantly increased radioactivity in the brain compared to WT animals,with more pronounced changes identified in the cortex and hippocampus.The translatability of this radiotracer for AD in a potential human use was supported by additional studies,including similar uptake profiles in non-human primates,an increase of HDAC6 in ADrelated human postmortem hippocampal tissues by Western blotting protein analysis,and our ex vivo histopathological analysis of HDAC6 in postmortem brain tissues of our animals.Collectively,our findings show that HDAC6 may lead to AD by mechanisms that tend to affect brain regions particularly susceptible to AD through an association with amyloid pathology.

Disease modification and Neuroprotection in neurodegenerative disorders

Background:Disease modifying therapies(DMTs)are urgently needed for neurodegenerative diseases(NDD)such as Alzheimer’s disease(AD)and many other disorders characterized by protein aggregation and neurodegeneration.Despite advances in understanding the neurobiology of NDD,there are no approved DMTs.Discussion:Defining disease-modification is critical to drug-development programs.A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death.A DMT is neuroprotective,and neuroprotection will result in disease modification.Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD.Alternatively,disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design.Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.Conclusion:Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death.Supporting data are collected in clinical trials.Effectively defining a DMT will assist in NDD drug development programs.

Extracellular Elastin Molecule Modulates Alzheimer’s AβDynamics In Vitro and In Vivo by Affecting Microglial Activities

Alzheimer’s disease(AD)is a neurodegenerative disorder,and the etiology of AD has not been completely elucidated.It remains unknown how the components from the brain’s extracellular matrix(ECM),particularly fibrous entities,may influence the pathogenesis of AD.Herein,we report that treatment with elastin-like polypeptides(ELPs),a component of the brain ECM,significantly increases the extracellular levels of AD-related amyloid-beta(Aβ)peptides and decreases intracellular Aβlevels in human microglial cell model HMC3 cells(HMC3).

Randomized controlled trials in frontotemporal dementia: cognitive and behavioral outcomes

Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia(FTD).Targets for intervention have been identified,therapies are being developed,and clinical trials are advancing.A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes.The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction,language impairments and behavioral disturbance.Behavioral variant FTD is characterized by an initial presentation of changes in personality,behavior and/or emotion,which are often difficult to objectively capture using traditional neuropsychological measures.The two principal language variants of FTD are Progressive Nonfluent Aphasia(PNFA)with predominant agrammatic/non-fluent impairments and Semantic Dementia(SD)with semantic impairments and visual agnosia.Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change,yet specific enough to isolate signal from noise,and acceptable to regulatory agencies.Given the anticipated potential for small effect sizes,measures must be able to identify small incremental changes over time.It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest.Selected outcome measures should be suitable for repeat administration,yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability.To facilitate widespread adoption as an endpoint,measures should be readily accessible.We provide several examples of potential global,composite,and individual cognitive measures,as well as behavioral measures promising for FTD trials.Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.