Neural network dysfunction in Alzheimer's disease: a drug development perspective

Over the last few years, a major focus of Alzheimer's disease research has been to understand the mechanisms by which build-up of the beta-amyloid protein (Abeta) in the brain leads to chronic neurodegeneration and eventual cell death. It is increasingly recognized that cell death is not a major cause of dementia. Indeed, recent studies suggest that Abeta causes neuritic dystrophy and interferes with mechanisms of synaptic plasticity such as long-term potentiation. There are also a number of well-described homeostatic mechanisms in the brain that help to maintain signal strength as a consequence of lowered synaptic input, which may occur as a consequence of neuritic dystrophy. This review examines mechanisms of synaptic scaling in the brain and explores prospects for future drug development based on a neural network perspective.