Staying Connected: Synapses in Alzheimer Disease

Abstract

Careful dissection is continuing to reveal the complexity and importance of synapse alterations in Alzheimer disease (AD). Synaptic alterations are the best biological correlate to the extent of cognitive loss1,2 and have become the gold standard of meaningful biomarkers of AD. Not neurofibrillary tangles (NFT), senile plaques, or even neuronal loss show such strong statistical correlation with dementia.2–4 Connections are the hallmark of neurons and without functional synapses, neurons are in “solitary.” Recent findings showing that amyloid-β (Aβ) affects and accumulates in synapses5 and that amyloid-β protein precursor (AβPP) over-expressing mice show synaptic alterations6,7 have provided additional evidence that synapses are a critical readout of the biology of AD. In this issue, Gylys and co-workers8 provide an elegant and precise dissection of synaptic alterations in AD using synaptosomal preparations. The results are both consistent with the synaptic alteration hypothesis proposed by Terry and colleagues2–4 and refine it. In previous studies synapses have been quantitated by synaptophysin immunoreactivity,1,9 a protein belonging to a subclass of synaptic vesicles. However, when synapses were quantitated by precise ultrastructural morphometric/stereological approaches, reduction in synapses was much less striking than the reduction in synaptophysin.10 Furthermore, synapse alterations included major remodeling of morphology11 as noted in some of the earliest studies of AD.12 These established findings lead one to consider whether the alterations in synapses in AD are limited to global reduction in vesicles rather than synapse changes. Gylys and collaborators8 used a broad range of pre- and postsynaptic markers to precisely analyze synaptosomes by flow cytometry. They found that the synaptosomes in AD show no reduction in synaptophysin and only a slight reduction in the overall number of synaptosomes. To account for the undoubted major reduction in synaptophysin while synapse number and synaptic vesicle number are only slightly reduced, brings to mind the seminal findings of Suzuki and Terry13 who reported substantial axonal transport abnormalities in AD. Consistently, one finds vesicle pile-up in cell bodies similar to transport blockage models.14 Recent findings that microtubules are greatly reduced in AD15 and that AβPP/Aβ play important roles in vesicular transport16–20 further link Terry’s transport and Gylys’ synaptic hypotheses. Not answered is where the extrasynaptic synaptophysin is located. One of the most attractive possibilities is that many of the synaptophysin vesicles are located in axons; for that reason, Terry’s initial insight to focus on vesicles was particularly fruitful because it marked the reduction most specific to AD. Additional work either by cell fractionation studies, as Gylys and collaborators8 have so elegantly performed, or by immunoelectron microscopy is called for to dissect this issue more clearly.