Alzheimer’s disease (AD) is a progressive neurocognitive disorder and the most common cause of dementia in the elderly. Plaques of amyloid-ß (Aß) peptides and neurofibrillary tangles of hyperphosphorylated tau protein are pathognomonic of AD and have been used to stage the progression of neuropathology in the AD brain. However, it is the degree of synaptic loss in the limbic system, basal forebrain, and the neocortex that has been shown to correlate the strongest with cognitive decline in AD patients. This significant clinicopathological correlation was reported more than 30 years ago and has placed the structure and function of synapses in the focus of AD research ever since.
Studies examining the molecular underpinnings of synaptic degeneration in AD have traditionally focused on Aß- and tau-induced synaptotoxicity. These pioneering studies have established that soluble oligomeric species, rather than insoluble plaques and tangles are the proteotoxic mediators that disrupt synapses during the course of AD. In recent years, genome-wide association and next-generation sequencing studies have identified several single nucleotide mutations in innate immunity genes as risk factors of sporadic AD. Accordingly, interactions between neurons and glial cells, notably microglia, have been increasingly scrutinized for their role in the synaptic failure of AD. In addition to Aß-, tau- and glial-mediated synaptic dysfunction and degeneration, disruption of energy metabolism that is directly or indirectly linked to AD pathology, has been shown to compromise the functional integrity of synapses in complex and even unexpected ways.
Developments in unraveling the mechanisms that drive synaptic degeneration and loss in AD have not been accompanied by equal progress in identifying markers of synaptic integrity and/or synaptic-protective strategies. Studies establishing a clear timeline of pre-, post-, and trans-synaptic changes during the progression of AD, and how these are associated with ?ß and tau pathology, glial activation, and innate immunity, are particularly scarce.
This Research Topic will provide an up-to-date overview of research efforts covering all aspects of synaptic pathology in AD, from molecular mechanisms to therapeutic strategies. We welcome contributions of original research articles, brief research reports, review and perspective articles that address but are not limited to, the following areas:
• Mechanistic studies of ?ß-, tau-, glia-, immune- and mitochondria-dependent synaptic loss or dysfunction;
• Longitudinal studies correlating synaptic pathology with markers of Aß pathology, tau pathology, glial activation, and markers of innate immune activation;
• Identification and validation of imaging and fluid biomarkers of pre-, post- or trans-synaptic damage;
• Pharmacological and non-pharmacological strategies of synaptic protection.
Alzheimer’s disease (AD) is a progressive neurocognitive disorder and the most common cause of dementia in the elderly. Plaques of amyloid-ß (Aß) peptides and neurofibrillary tangles of hyperphosphorylated tau protein are pathognomonic of AD and have been used to stage the progression of neuropathology in the AD brain. However, it is the degree of synaptic loss in the limbic system, basal forebrain, and the neocortex that has been shown to correlate the strongest with cognitive decline in AD patients. This significant clinicopathological correlation was reported more than 30 years ago and has placed the structure and function of synapses in the focus of AD research ever since.
Studies examining the molecular underpinnings of synaptic degeneration in AD have traditionally focused on Aß- and tau-induced synaptotoxicity. These pioneering studies have established that soluble oligomeric species, rather than insoluble plaques and tangles are the proteotoxic mediators that disrupt synapses during the course of AD. In recent years, genome-wide association and next-generation sequencing studies have identified several single nucleotide mutations in innate immunity genes as risk factors of sporadic AD. Accordingly, interactions between neurons and glial cells, notably microglia, have been increasingly scrutinized for their role in the synaptic failure of AD. In addition to Aß-, tau- and glial-mediated synaptic dysfunction and degeneration, disruption of energy metabolism that is directly or indirectly linked to AD pathology, has been shown to compromise the functional integrity of synapses in complex and even unexpected ways.
Developments in unraveling the mechanisms that drive synaptic degeneration and loss in AD have not been accompanied by equal progress in identifying markers of synaptic integrity and/or synaptic-protective strategies. Studies establishing a clear timeline of pre-, post-, and trans-synaptic changes during the progression of AD, and how these are associated with ?ß and tau pathology, glial activation, and innate immunity, are particularly scarce.
This Research Topic will provide an up-to-date overview of research efforts covering all aspects of synaptic pathology in AD, from molecular mechanisms to therapeutic strategies. We welcome contributions of original research articles, brief research reports, review and perspective articles that address but are not limited to, the following areas:
• Mechanistic studies of ?ß-, tau-, glia-, immune- and mitochondria-dependent synaptic loss or dysfunction;
• Longitudinal studies correlating synaptic pathology with markers of Aß pathology, tau pathology, glial activation, and markers of innate immune activation;
• Identification and validation of imaging and fluid biomarkers of pre-, post- or trans-synaptic damage;
• Pharmacological and non-pharmacological strategies of synaptic protection.