Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. The pathological accumulation of tau in neurons is one of the hallmarks of AD and has been connected to the loss of dendritic spines of pyramidal cells, which are the major targets of cortical excitatory synapses and key elements in memory storage. However, the detailed mechanisms underlying the loss of dendritic spines in individuals with AD are still unclear. Here, we used graph-theory approaches to compare the distribution of dendritic spines from neurons with and without tau pathology of AD individuals. We found that the presence of tau pathology determines the loss of dendritic spines in clusters, ruling out alternative models where spine loss occurs at random locations. Since memory storage has been associated with synaptic clusters, the present results provide a new insight into the mechanisms by which tau drives synaptic damage in AD, paving the way to memory deficits through alterations of spine organization.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity
These analyses indicate that the mechanism underlying the distinct organization pattern in dendrites with tau pathology entails the loss of blocks of spines
The understanding of how spines are lost in AD is still unclear but could potentially reveal the mechanisms underlying synaptic damage in this disorder
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a deterioration of neuronal connectivity. We overcame these issues by intracellularly injecting with Lucifer yellow (LY), neurons within a short time window post mortem and by excluding those in advanced tau stages or in contact with plaques This permits us to identify 6 neurons with 11 dendrites and 4204 spines for further analysis obtained from the hippocampal subfield Cornu Ammonis 1 (CA1) of an AD individual. Building on previous evidence showing that spines are organized in groups[18], we hypothesized that the pathological changes occurring in AD do not target single spines at random locations along the dendrite, but instead damage clusters of spines that are close to each other To test this hypothesis, we used an approach based on graph theory, where we modeled each dendrite as an ensemble of nodes connected by edges, where the nodes correspond to spines and the edges represent physical closeness between them (i.e., the inverse distance between the spines along the dendrite). These results provide an important insight into the mechanisms underlying synaptic degeneration in AD by showing that spines are lost in clusters in AD individuals
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