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Abstract
Dynamic gain and loss of synapses is fundamental to healthy brain function. While Alzheimer’s Disease (AD) treatment strategies have largely focussed on beta-amyloid and tau protein pathologies, the synapse itself may also be a critical endpoint to consider regarding disease modification. Disruption of mechanisms of neuronal plasticity, eventually resulting in a net loss of synapses, is implicated as an early pathological event in AD. Synaptic dysfunction therefore may be a final common biological mechanism linking protein pathologies to disease symptoms. This review summarizes evidence supporting the idea of early neuroplastic deficits being prevalent in AD. Changes in synaptic density can occur before overt neurodegeneration and should not be considered to uniformly decrease over the course of the disease. Instead, synaptic levels are influenced by an interplay between processes of degeneration and atrophy, and those of maintenance and compensation at regional and network levels. How these neuroplastic changes are driven by amyloid and tau pathology are varied. A mixture of direct effects of amyloid and tau on synaptic integrity, as well as indirect effects on processes such as inflammation and neuronal energetics are likely to be at play here. Focussing on the synapse and mechanisms of neuroplasticity as therapeutic opportunities in AD raises some important conceptual and strategic issues regarding translational research, and how preclinical research can inform clinical studies. Nevertheless, substrates of neuroplasticity represent an emerging complementary class of drug target that would aim to normalize synapse dynamics and restore cognitive function in the AD brain and in other neurodegenerative diseases.
Highlights
Specialty section: This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
While Alzheimer’s Disease (AD) treatment strategies have largely focussed on beta-amyloid and tau protein pathologies, the synapse itself may be a critical endpoint to consider regarding disease modification
This review summarizes evidence supporting the idea of early neuroplastic deficits being prevalent in AD
Summary
At the most general level, plasticity refers to the ability of the nervous system to dynamically modulate its function in response to ongoing internal activities or external experiences. Plasticity is a normal and essential part of cognition, an important means by which the brain can respond to damage. Plasticity can be conceptualized and defined at several different levels of function, from basic biochemical events to integrated behavioral responses (Figure 1). Structural plasticity relates to the physical morphology of synapses. The term synaptic plasticity per se is most typically used to describe processes related to the efficiency of transmission across new or existing synapses. A fundamental concept linking structural and synaptic plasticity is Hebbian learning (Hebb, 1949), where a threshold of coincident activity at synapses between cells will result
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