Synaptic Disruption by Soluble Oligomers in Patients with Alzheimer's and Parkinson's Disease

Neurodegenerative diseases are the result of progressive dysfunction of the neuronal activity and subsequent neuronal death. Currently, the most prevalent neurodegenerative diseases are by far Alzheimer's (AD) and Parkinson's (PD) disease, affecting millions of people worldwide. Although amyloid plaques and neurofibrillary tangles are the neuropathological hallmarks for AD and Lewy bodies (LB) are the hallmark for PD, current evidence strongly suggests that oligomers seeding the neuropathological hallmarks are more toxic and disease-relevant in both pathologies. The presence of small soluble oligomers is the common bond between AD and PD: amyloid beta oligomers (A beta Os) and Tau oligomers (TauOs) in AD and alpha-synuclein oligomers (alpha SynOs) in PD. Such oligomers appear to be particularly increased during the early pathological stages, targeting synapses at vulnerable brain regions leading to synaptic plasticity disruption, synapse loss, inflammation, excitation to inhibition imbalance and cognitive impairment. Absence of TauOs at synapses in individuals with strong AD disease pathology but preserved cognition suggests that mechanisms of resilience may be dependent on the interactions between soluble oligomers and their synaptic targets. In this review, we will discuss the current knowledge about the interactions between soluble oligomers and synaptic dysfunction in patients diagnosed with AD and PD, how it affects excitatory and inhibitory synaptic transmission, and the potential mechanisms of synaptic resilience in humans.

Automated summary

Neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, result from the dysfunction and death of neurons. The presence of small soluble oligomers, such as amyloid beta and Tau oligomers in Alzheimer's, and alpha-synuclein oligomers in Parkinson's, is toxic and relevant to the development of these diseases. These oligomers increase during the early stages of pathology, leading to disruption of synaptic plasticity, synapse loss, inflammation, imbalance between excitatory and inhibitory transmission, and cognitive impairment. The absence of Tau oligomers at synapses in individuals with advanced Alzheimer's pathology but preserved cognition suggests that resilience mechanisms may depend on the interactions between soluble oligomers and their synaptic targets.