Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Abstract

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, and synapse loss is, to date, one of the main biological correlates of cognitive decline within Alzheimer’s disease. This occurs prior to neuronal loss with ample evidence that synaptic dysfunction precedes this, in support of the idea that synaptic failure is a crucial stage within disease pathogenesis. The two main pathological hallmarks of Alzheimer’s disease, abnormal aggregates of amyloid or tau proteins, have had demonstrable effects on synaptic physiology in animal and cellular models of Alzheimer’s disease. There is also growing evidence that these two proteins may have a synergistic effect on neurophysiological dysfunction. Here, we review some of the main findings of synaptic alterations in Alzheimer’s disease, and what we know from Alzheimer’s disease animal and cellular models. First, we briefly summarize some of the human evidence to suggest that synapses are altered, including how this relates to network activity. Subsequently, animal and cellular models of Alzheimer’s disease are considered, highlighting mouse models of amyloid and tau pathology and the role these proteins may play in synaptic dysfunction, either in isolation or examining how the two pathologies may interact in dysfunction. This specifically focuses on neurophysiological function and dysfunction observed within these animal models, typically measured using electrophysiology or calcium imaging. Following synaptic dysfunction and loss, it would be impossible to imagine that this would not alter oscillatory activity within the brain. Therefore, this review also discusses how this may underpin some of the aberrant oscillatory patterns seen in animal models of Alzheimer’s disease and human patients. Finally, an overview of some key directions and considerations in the field of synaptic dysfunction in Alzheimer’s disease is covered. This includes current therapeutics that are targeted specifically at synaptic dysfunction, but also methods that modulate activity to rescue aberrant oscillatory patterns. Other important future avenues of note in this field include the role of non-neuronal cell types such as astrocytes and microglia, and mechanisms of dysfunction independent of amyloid and tau in Alzheimer’s disease. The synapse will certainly continue to be an important target within Alzheimer’s disease for the foreseeable future.

AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons

“…This deficit correlates with phenotypic deficits in synaptic activity (Figures 5-7). While synaptic dysfunction and loss of synaptic connections occurs in numerous neurodegenerative diseases, such as Huntington Disease (HD) 56,57 , C9orf72 FTD/ALS 58,59 , and Alzheimer Disease (AD) 60,61 , the molecular steps preceding this deficit in synaptic gene expression and associated synaptic dysfunction in CANVAS patient neurons is unclear. Intriguingly, monoallelic deletion of the AAGGG expansion significantly corrected both synaptic gene expression defects and synaptic signaling dysfunction in CANVAS neurons (Figure 6).…”

Development of a three-dimensional organoid model to explore early retinal phenotypes associated with Alzheimer’s disease

“…It was notable that we observed changes in the expression levels of genes related to synaptic connectivity, in line with studies suggesting that a loss of synaptic connectivity may also be an early indicator of AD pathology that occurs before the onset of plaque deposition 54 , 55 . While previous studies have demonstrated synaptic dysregulation in AD 56 – 58 , there are limited analyses of synaptic dysfunction in the retina associated with AD. Thus, these studies represent an important direction for early phenotypes within the retina that may aid in the identification of AD phenotypes observed before clinical phenotypes manifest, aiding in future translational applications that could help to better understand how preclinical alterations in AD affect disease progression.…”

Another Use for a Proven Drug: Experimental Evidence for the Potential of Artemisinin and Its Derivatives to Treat Alzheimer’s Disease

“…Synapse dysfunction is thought to start long before the loss of memory and accelerate as the disease progress. There are widespread changes in synapse number, size, shape and structure of synaptic protein expression in AD brains, all suggestive of synaptic dysfunction that, predictably, will lead to changes in network oscillations [132,133]. There is evidence of a disrupted balance between excitatory and inhibitory neuronal activities (E/I imbalance) early before the onset of clinical symptoms, both in AD patients and animal models, and is seen as a main driver of AD pathogenesis promoting cognitive deficits [134,135].…”