Restoring synaptic function through multimodal therapeutics

Alzheimer's disease (AD) is the major form of dementia and a growing epidemic for which no disease-modifying treatments exist. AD is characterized by the early loss of synapses in the brain and, at later stages, neuronal death accompanied with progressive loss of cognitive functions. Here we focus on the mechanisms involved in the maintenance of the synapse and how their perturbation leads to synaptic loss. We suggest treatment strategies that particularly target energy metabolism in terms of cholesterol and glucose biochemistry in neurons and astrocytes We also discuss the potential of restoring impaired protein homeostasis through autophagy. These pathways are analyzed from a basic science perspective and suggest new avenues for discovery. We also propose several targets for both basic and translational therapeutics in these pathways and provide perspective on future AD treatment.