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 pri...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).展开更多
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 f...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.展开更多
BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes ...BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer’s disea se located near a well-established linkage peak on chromosome 9q22. METHODS:We evaluated 19 single-nucleotide polymorphisms in three genes within the chromoso me 9q linkage region in 437 multiplex families with Alzheimer’s disease from th e National Institute of Mental Health (NIMH) sample (1439 subjects). We then tes ted the single-nucleotide polymorphisms showing a positive result in an indepen dently identified set of 217 sibships discordant for Alzheimer’s disease (Conso rtium on Alzheimer’s Genetics [CAG] sample; 489 subjects) and assessed the func tional effect of an implicated single-nucleotide polymorphism in brain tissue f rom 25 patients with Alzheimer’s disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer’s disease and v arious single-nucleotide polymorphisms in UBQLN1. We confirmed these associatio ns in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alterna tively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain sa mples of patients with Alzheimer’s disease. CONCLUSIONS: Our findings suggest t hat genetic variants in UBQLN1 on chromosome 9q22 substantially increase the ris k of Alzheimer’s disease, possibly by influencing alternative splicing of this gene in the brain.展开更多
Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the format...Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.展开更多
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...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.展开更多
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 ...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).展开更多
Amyloid-b-protein(Ab),the key component of senile plaques in Alzheimer’s disease(AD)brain,is produced from amyloid precursor protein(APP)by cleavage of b-secretase and then g-secretase.APP adaptor proteins with phosp...Amyloid-b-protein(Ab),the key component of senile plaques in Alzheimer’s disease(AD)brain,is produced from amyloid precursor protein(APP)by cleavage of b-secretase and then g-secretase.APP adaptor proteins with phosphotyrosine-binding(PTB)domains,including Dab(gene:DAB)and Numb(gene:NUMB),can bind to and interact with the conserved YENPTY-motif in the APP C-terminus.Here we describe,for the first time,the effects of RNAi knock-down of Dab and Numb expression on APP processing and Ab production.RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP(H4-FL-APP cells)or APP-C99(H4-APP-C99 cells)increased levels of APP-C-terminal fragments(APP-CTFs)and lowered Ab levels in both cell lines by inhibiting g-secretase cleavage of APP.Finally,RNAi knock-down of APP also reduced levels of Numb in H4-APP cells.These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD.The notion of attenuating g-secretase cleavage of APP via the APP adaptor proteins,Dab and Numb,is particularly attractive with regard to therapeutic potential,given that side effects of gsecretase inhibition owing to impaired proteolysis of other g-secretase substrates,e.g.Notch,might be avoided.展开更多
基金supported by the Massachusetts General Hospital Scientific Projects to Accelerate Research and Collaboration (SPARC) awardCure Alzheimer’s Fund (to CZ)the National Institutes of Health (NIH),including R01NS102190,RF1NS120947,and R01HL161253 (to MBW),RF1NS120947 (to RJT)。
文摘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).
基金supported by Cure Alzheimer’s Fund(to RET and SHC)JPB Foundation(to RET),and R56AG072054(to SHC)。
文摘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.
文摘BACKGROUND: Recent analyses suggest that the known Alzheimer’s disease genes account for less than half the genetic variance in this disease. The gene encodi ng ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer’s disea se located near a well-established linkage peak on chromosome 9q22. METHODS:We evaluated 19 single-nucleotide polymorphisms in three genes within the chromoso me 9q linkage region in 437 multiplex families with Alzheimer’s disease from th e National Institute of Mental Health (NIMH) sample (1439 subjects). We then tes ted the single-nucleotide polymorphisms showing a positive result in an indepen dently identified set of 217 sibships discordant for Alzheimer’s disease (Conso rtium on Alzheimer’s Genetics [CAG] sample; 489 subjects) and assessed the func tional effect of an implicated single-nucleotide polymorphism in brain tissue f rom 25 patients with Alzheimer’s disease and 17 controls. RESULTS: In the NIMH sample, we observed a significant association between Alzheimer’s disease and v arious single-nucleotide polymorphisms in UBQLN1. We confirmed these associatio ns in the CAG sample. The risk-conferring haplotype in both samples was defined by a single intronic single-nucleotide polymorphism located downstream of exon 8. The risk allele was associated with a dose-dependent increase in an alterna tively spliced UBQLN1 (lacking exon 8) transcript in RNA extracted from brain sa mples of patients with Alzheimer’s disease. CONCLUSIONS: Our findings suggest t hat genetic variants in UBQLN1 on chromosome 9q22 substantially increase the ris k of Alzheimer’s disease, possibly by influencing alternative splicing of this gene in the brain.
基金supported by the National Natural Science Foundation of China(22020102003,22388101,22125701,22277064)National Key R&D Program of China(2021YFF1200300,2021YFF0701800,and 2022YFF0710000)China Postdoctoral Science Foundation(2022M711785)。
文摘Although there are no effective therapies to block or reverse Alzheimer’s disease(AD)progression at present,a promising therapeutic strategy is to reduce levels of amyloid𝛽(Aβ)proteins,which drive the formation of amyloid plaque,a primary hallmark in AD brains.Herein,we report that amphiphilic lipid-DNA molecules(LD)were designed by incorporating a long alkyl chain into the nucleotide base.It significantly down-regulated Alzheimer’s Aβ levels in vivo and in vitro.In contrast to small-molecule chemical drugs and antibody therapies,the assembled DNA nanoparticles allowed them to effectively cross the blood-brain barrier(BBB)and accumulate in the brain,increasing the therapeutic effects.Notably,lipid-DNA downregulated the levels of Aβ peptides significantly in vitro.AD mice model experiments demonstrated that the LD-treated groups exhibited a rapid cognition behavioral improvement,which was associated with brain engagement of LD and reduced Aβ levels.Thus,the molecularly engineered DNA nanomaterials effectively regulated Aβ peptides.This work might provide a promising DNA engineering strategy for AD treatment.
基金supported by pilot funding from the Martinos Center (to Changning Wang, USA)the Cure Alzheimer’s Fund, USA
文摘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.
基金from National Key R&D Program of China(grant no.2018YFA0902600)the Scientific Instrument Developing Project of the Chinese Academy of Sciences(grant no.ZDKYYQ20180001)+1 种基金the Jilin Province Science Fund for Excellent Young Scholars(20190103072JH),K.C.Wong Education Foundation(grant no.GJTD-2018-09)and the National Natural Science Foundation of China(grant nos.21704099,21877104,and 21834007)and the Cure Alzheimer’s Fund.
文摘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).
基金This research was supported by K08NS048140,R21AG029856,R21AG038994 and R01 GM088801(National Institutes of Health),USA,Jahnigen Career Development Award(American Geriatrics Society),USAInvestigator Initiated Research Grant(Alzheimer’s Association),Cure Alzheimer’s Fund,USA(to Z.X.)MH 60009(National Institute of Mental Health),USA,Cure Alzheimer’s Fund(to R.T.).
文摘Amyloid-b-protein(Ab),the key component of senile plaques in Alzheimer’s disease(AD)brain,is produced from amyloid precursor protein(APP)by cleavage of b-secretase and then g-secretase.APP adaptor proteins with phosphotyrosine-binding(PTB)domains,including Dab(gene:DAB)and Numb(gene:NUMB),can bind to and interact with the conserved YENPTY-motif in the APP C-terminus.Here we describe,for the first time,the effects of RNAi knock-down of Dab and Numb expression on APP processing and Ab production.RNAi knock-down of Dab and Numb in H4 human neuroglioma cells stably transfected to express either FL-APP(H4-FL-APP cells)or APP-C99(H4-APP-C99 cells)increased levels of APP-C-terminal fragments(APP-CTFs)and lowered Ab levels in both cell lines by inhibiting g-secretase cleavage of APP.Finally,RNAi knock-down of APP also reduced levels of Numb in H4-APP cells.These findings suggest that pharmacologically blocking interaction of APP with Dab and Numb may provide novel therapeutic strategies of AD.The notion of attenuating g-secretase cleavage of APP via the APP adaptor proteins,Dab and Numb,is particularly attractive with regard to therapeutic potential,given that side effects of gsecretase inhibition owing to impaired proteolysis of other g-secretase substrates,e.g.Notch,might be avoided.
