Targeting synaptic pathology in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by memory and cognitive impairments.The two primary pathological hallmarks of AD include the accumulation ofβ-amyloid(Aβ)plaques and formation of neurofibrillary tangles(NFTs)composed predominantly of hyperphosphorylated tau protein(Zhang et al.,2023).Moreover,synaptic dysfunction is considered another crucial factor in AD pathogenesis and is closely associated with cognitive decline.Notably,synaptic damage,loss,and dysfunction manifest earlier than the pathological features of Aβplaques and NFTs(Knopman et al.,2021).Therefore,understanding the mechanisms underlying synaptic dysfunction in AD is vital for providing insights into disease mechanisms and developing novel therapeutic strategies.

Long-term potentiation-based screening identifies neuronal PYGM as a synaptic plasticity regulator participating in Alzheimer's disease

Synaptic dysfunction is an important pathological hallmark and cause of Alzheimer's disease(AD).High-frequency stimulation(HFS)-induced long-term potentiation(LTP)has been widely used to study synaptic plasticity,with impaired LTP found to be associated with AD.However,the exact molecular mechanism underlying synaptic plasticity has yet to be completely elucidated.Whether genes regulating synaptic plasticity are altered in AD and contribute to disease onset also remains unclear.Herein,we induced LTP in the hippocampal CA1 region of wildtype(WT)and AD model mice by administering HFS to the CA3 region and then studied transcriptome changes in the CA1 region.We identified 89 genes that may participate in normal synaptic plasticity by screening HFS-induced differentially expressed genes(DEGs)in mice with normal LTP,and 43 genes that may contribute to synaptic dysfunction in AD by comparing HFS-induced DEGs in mice with normal LTP and AD mice with impaired LTP.We further refined the 43 genes down to 14 by screening for genes with altered expression in pathological-stage AD mice without HFS induction.Among them,we found that the expression of Pygm,which catabolizes glycogen,was also decreased in AD patients.We further demonstrated that down-regulation of PYGM in neurons impaired synaptic plasticity and cognition in WT mice,while its overexpression attenuated synaptic dysfunction and cognitive deficits in AD mice.Moreover,we showed that PYGM directly regulated energy generation in neurons.Our study not only indicates that PYGM-mediated energy production in neurons plays an important role in synaptic function,but also provides a novel LTP-based strategy to systematically identify genes regulating synaptic plasticity under physiological and pathological conditions.

VUV Photoionization Study of the Allyl Radical from Premixed Gasoline/Oxygen Flame

The allyl radical has been observed in a low-pressure premixed gasoline/oxygen/argon flame by using tunable vacuum ultraviolet photoionization mass spectrometry, The ionization potential of the allyl radical is derived to be （8.13 ±0.02） eV from photoionization efficiency curve, In addition, a high level ab initzo Gaussian-3 （G3） method was used to calculate the energies of tile radical and its cation. The calculated adiabatic ionization potential is 8.18 eV, which is in excellent agreement with the experimental value. The result is helpful for identifying the allyl radical formed from other flames and for understanding the mechanism of soot formation.

Alteration of β-secretase traffic by the receptor tyrosine kinase signaling pathway- a new mechanism for regulating Alzheimer's β-amyloid production

The receptor tyrosine kinases (RTKs) are a family of cellsurface proteins with diverse functions in proliferation, dif-ferentiation or cell-cell communication. When a specific li-gand binds to its cognate receptor, a conformational changeof this receptor due to the ligand-receptor interaction willlead to activation of the intrinsic tyrosine kinase residing inthe intracellular domain of the receptor. The activation ofthis tyrosine kinase is essential for transducing the signals toa cascade of its downstream molecules that eventually causerelated physiological responses [1]. For example, binding ofnerve growth factor (NGF) to its receptor TrkA is essentialfor the proper development, patterning, and maintenanceof the mammalian nervous system. This ligand and recep-tor interaction will lead to the formation of a crab-shapedhomodimeric TrkA structure [2], and the subsequent activa-tion of its intrinsic RTK will cause auto-phosphorylationof its own intracellular tyrosine residues. PhosphorylatedTrkA receptors recruit and increase the phosphorylationof PLC-γ and Shc, which leads to activation of either thePI3K/Akt pathway or Ras/raf/ERK pathway. In the brainOf Alzheimer's disease (AD) patients, alterations of nervegrowth factor (NGF) and its receptor TrkA have beenreported to associate with AD pathogenesis [3]. However,the underlying mechanisms remain elusive.

Biomarkers of aging

Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.

Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer＇s Disease

Objective：To review recent research advances on tau,a major player in Alzheimer＇s disease （AD） pathogenesis,a biomarker for AD onset,and potential target for AD therapy.Data Sources：This review was based on a comprehensive search using online literature databases,including PubMed,Web of Science,and Google Scholar.Study Selection：Literature search was based on the following keywords：Alzheimer＇s disease,tau protein,biomarker,cerebrospinal fluid （CSF）,therapeutics,plasma,imaging,propagation,spreading,seeding,prion,conformational templating,and posttranslational modification.Relevant articles were carefully reviewed,with no exclusions applied to study design and publication type.Results：Amyloid plaques enriched with extracellular amyloid beta （Aβ） and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks ofAD.Although the Aβ hypothesis has dominated AD research for many years,clinical Aβ-targeting strategies have consistently failed to effectively treat AD or prevent AD onset.The research focus in AD has recently shifted to the role oftau in AD.In addition to phosphorylation,tau is acetylated and proteolytically cleaved,which also contribute to its physiological and pathological functions.Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis.Techniques to detect tau at minute levels in CSF and blood have been developed,and improved tracers have facilitated tau imaging in the brain.These advances have potential to accurately determine tau levels at early diagnostic stages in AD.Given that tau is a potential therapeutic target,anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention.Conclusion：Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD.

M1 muscarinic acetylcholine receptor in Alzheimer's disease

The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer＇s disease （AD）. Muscarinic acetylcholine receptors （mAChRs） mediate acetylcholine-induced neurotransmission and five mAChR subtypes （M1-M5） have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists forAD treatment.

APOE interacts with ACE2 inhibitingg SARS-CoV-2 cellular entry and inflammation in COVID-19 patients

Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol metabolism.The APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases.Although APOE has recently been associated with increased susceptibility to infections of several viruses,whether and how APOEand its isoforms affect SARS-CoV-2 infection remains unclear.Here,we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients.Utilizing multiple protein interaction assays,we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2;and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2,a key docking site for SARS-CoV-2 Spike protein.In addition,immuno-imaging assays using confocal,super-resolution,and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spikemediated viral entry into cells.Interestingly,while having a comparable binding affinity to ACE2,APOE4 inhibits viral entry to a lesser extent compared to APOE3,which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2.Furthermore,APOE e4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed.Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2,which may explain in part increased COVID-19 infection and disease severity in APOE e4 carriers.