Cutting the Synaptic Cord

Cutting the Synaptic Cord

The earliest steps in Alzheimer's disease have proven tricky to target with therapeutics because they occur as part of normal brain activity and before symptom onset. This pathway now has been fleshed out by a trio of papers that have mapped a sequence of synaptic events leading to b-amyloid production and its sequelae, pointing to new therapeutic targets and drug delivery strategies (see Figure 1, "Mapping early Alzheimer's disease events and targets").

Two studies1,2 address the endosomal processing events that occur within neuronal cells to convert amyloid precursor protein (APP) to b-amyloid (Ab), which is the major constituent of the amyloid plaques that are the hallmarks of AD.3

The third study tackles the consequences of Ab exposure on signaling pathways in neurons and identifies a phosphoinositide called phophatidylinositol-4,5-bisphosphate (PIP2) as a potentially neuroprotective target.4The work has led to the formation of drug discovery company Smart Biosciences Inc.

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The first report, published in Neuron by a group at Washington University School of Medicine, shows how synaptic activity increases the production of Ab fragments. The study used an in vivo microdialysis procedure to monitor levels of Ab in the fluid that surrounds brain cells. The researchers discovered that electrical stimulation of neurons caused a sharp spike in the production of Ab found in the fluid surrounding brain cells.

Lead author John Cirrito, research instructor at Washington University's Department of Neurology, told SciBX that his work shows in real time how the toxic Ab fragment is made. The key step, Cirrito said, is endocytosis of membrane-bound APP upon neuron stimulation.

The proof was the finding

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