As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The r...As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The registration networks have collected hundreds of pedigrees, for which genetic screening, neuropsycholog-ical tests and amyloid and tau imaging was used to study diagnostic biomarkers for preclinical and mild cognitive impairment （MCI） stages of AD. Besides identifying ped-igrees with novel mutations in presenilins （PSENs）/amy-loid precursor protein （APP）, the program has benefted training of Chinese research fellows, AD clinical trials forprevention,the ethical concernsfor clinical fndings, and other collaborative projects with Chinese investiga-tors. Further research of the collaborative program may facilitate the testing and clinical use of novel treatments for EOFAD and late onset AD and contribute to dementia prevention strategies in Canada and China.展开更多
Nerve growth factor(NGF) is a neurotrophic factor critical for cholinergic neuronal survival, phenotypic maintenance and plasticity in the mammalian brain. NGF has been implicated in the pathogenesis of neurodegenerat...Nerve growth factor(NGF) is a neurotrophic factor critical for cholinergic neuronal survival, phenotypic maintenance and plasticity in the mammalian brain. NGF has been implicated in the pathogenesis of neurodegenerative disorders, with direct administration of NGF into the brain capable of facilitating neuroprotection and repair.展开更多
Background Cognitive reserve allows for resilience to neuropathology,potentially through active compensation.Here,we examine ex vivo electrophysiological evidence for active compensation in Alzheimer’s disease(AD)foc...Background Cognitive reserve allows for resilience to neuropathology,potentially through active compensation.Here,we examine ex vivo electrophysiological evidence for active compensation in Alzheimer’s disease(AD)focusing on the cholinergic innervation of layer 6 in prefrontal cortex.Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models,and their modulation of deep layer prefrontal cortex is essential for attention and executive function.Methods We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models:a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD.We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.Results In two AD models,we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology.To identify the locus of this enhanced cholinergic signal,we dissected key pre-and post-synaptic components with pharmacological strategies.We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons.To probe the additional impact of therapeutic intervention on the adapted circuit,we tested cholinergic and nicotinic-selective pro-cognitive treatments.Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics.Positive allosteric modulation of nicotinic receptors,by contrast,enhanced endogenous cholinergic responses and retained their rapid kinetics.Conclusions We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models.Promisingly,this nicotinic signal can be further enhanced while preserving its rapid kinetic signature.Taken together,our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation,highlighting a new direction for cognitive treatment in AD neuropathology.展开更多
文摘As biomarkers are important in the early diagnosis ofAlzheimer’s disease （AD）, the frst collab-orative work of recruiting early-onset familial AD （EO-FAD） families in Canada and China was initiated in 2012. The registration networks have collected hundreds of pedigrees, for which genetic screening, neuropsycholog-ical tests and amyloid and tau imaging was used to study diagnostic biomarkers for preclinical and mild cognitive impairment （MCI） stages of AD. Besides identifying ped-igrees with novel mutations in presenilins （PSENs）/amy-loid precursor protein （APP）, the program has benefted training of Chinese research fellows, AD clinical trials forprevention,the ethical concernsfor clinical fndings, and other collaborative projects with Chinese investiga-tors. Further research of the collaborative program may facilitate the testing and clinical use of novel treatments for EOFAD and late onset AD and contribute to dementia prevention strategies in Canada and China.
基金supported by the Canadian Institutes of Health Research(grant FRN 137064 to IA)the FDC Foundation+3 种基金the WB Family FoundationGerald and Carla Connor,the Weston Brain Institute(TR130117 to IA)a Frederick Banting and Charles Best Canada Graduate Scholarship(GSD 152271 to KX)in part,from funding through the Canada Research Chairs program(to IA)。
文摘Nerve growth factor(NGF) is a neurotrophic factor critical for cholinergic neuronal survival, phenotypic maintenance and plasticity in the mammalian brain. NGF has been implicated in the pathogenesis of neurodegenerative disorders, with direct administration of NGF into the brain capable of facilitating neuroprotection and repair.
基金funded by research grants from the Canadian Institutes of Health(CIHR):MOP 89825,EKLPRJ153101,EKL and JMsupport of a CIHR Banting and Best Canada Graduate Scholarship and an Ontario Graduate Scholarship,SKP.
文摘Background Cognitive reserve allows for resilience to neuropathology,potentially through active compensation.Here,we examine ex vivo electrophysiological evidence for active compensation in Alzheimer’s disease(AD)focusing on the cholinergic innervation of layer 6 in prefrontal cortex.Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models,and their modulation of deep layer prefrontal cortex is essential for attention and executive function.Methods We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models:a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD.We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.Results In two AD models,we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology.To identify the locus of this enhanced cholinergic signal,we dissected key pre-and post-synaptic components with pharmacological strategies.We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons.To probe the additional impact of therapeutic intervention on the adapted circuit,we tested cholinergic and nicotinic-selective pro-cognitive treatments.Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics.Positive allosteric modulation of nicotinic receptors,by contrast,enhanced endogenous cholinergic responses and retained their rapid kinetics.Conclusions We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models.Promisingly,this nicotinic signal can be further enhanced while preserving its rapid kinetic signature.Taken together,our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation,highlighting a new direction for cognitive treatment in AD neuropathology.
