Synapse pathology in Alzheimer’s disease

• Published in: Seminars in cell & developmental biology 2023-04, Vol.139, p.13-23
• Main Authors: Griffiths, Jessica, Grant, Seth G.N.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer’s disease; Brain - pathology; Humans; Learning; Microscopy; Neuroglia - pathology; Synapse; Synapses - physiology; Synaptome; Tau
• ISSN: 1084-9521; 1096-3634
• DOI: 10.1016/j.semcdb.2022.05.028

Synapse loss and damage are central features of Alzheimer’s disease (AD) and contribute to the onset and progression of its behavioural and physiological features. Here we review the literature describing synapse pathology in AD, from what we have learned from microscopy in terms of its impacts on synapse architecture, to the mechanistic role of Aβ, tau and glial cells, mitochondrial dysfunction, and the link with AD risk genes. We consider the emerging view that synapse pathology may operate at a further level, that of synapse diversity, and discuss the prospects for leveraging new synaptome mapping methods to comprehensively understand the molecular properties of vulnerable and resilient synapses. Uncovering AD impacts on brain synapse diversity should inform therapeutic approaches targeted at preserving or replenishing lost and damaged synapses and aid the interpretation of clinical imaging approaches that aim to measure synapse damage. •Loss of synapses and changes in their morphology are well described in Alzheimer’s disease.•Aβ and tau target both presynaptic and postsynaptic proteins.•Synapse pathology also involves mitochondrial dysfunction and glial cell interactions.•The impact of Alzheimer’s disease on synapse molecular diversity is poorly understood.•Synaptome mapping could be used to identify and characterise vulnerable and resilient synapses in Alzheimer’s disease.