Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link b...Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.展开更多
Vascular damage plays a significant role in the onset and progression of Alzheimer’s disease(AD).However,the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear....Vascular damage plays a significant role in the onset and progression of Alzheimer’s disease(AD).However,the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear.The present study aimed to examine the impact of fibrinogen(Fg)on tau pathology.The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau,enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation.Notably,Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils.Furthermore,intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology,neuroinflammation,synaptic damage,neuronal apoptosis,and cognitive dysfunction in tau P301S mice compared to controls.The present study provides compelling evidence linking Fg and tau,thereby connecting cerebrovascular damage to tau pathology in AD.Consequently,inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.展开更多
文摘Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.
基金supported by a grant from the National Natural Science Foundation of China(82071183).
文摘Vascular damage plays a significant role in the onset and progression of Alzheimer’s disease(AD).However,the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear.The present study aimed to examine the impact of fibrinogen(Fg)on tau pathology.The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau,enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation.Notably,Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils.Furthermore,intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology,neuroinflammation,synaptic damage,neuronal apoptosis,and cognitive dysfunction in tau P301S mice compared to controls.The present study provides compelling evidence linking Fg and tau,thereby connecting cerebrovascular damage to tau pathology in AD.Consequently,inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
