Clusterin accumulates in synapses in Alzheimer's disease and is increased in apolipoprotein E4 carriers.

Rosemary J Jackson,Tara L Spires-Jones,Colin Smith,Chris Henstridge,Jane Tulloch,Jamie Rose

doi:10.1093/braincomms/fcz003

Rosemary J Jackson, Tara L Spires-Jones + Show 4 more

Open Access

https://doi.org/10.1093/braincomms/fcz003

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Abstract

One of the major challenges in developing effective therapeutic strategies for Alzheimer's disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer's. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer's and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer's and support a potential role for clusterin working with APOE in causing synaptic damage.

Highlights

Alzheimer’s disease, a devastating neurodegenerative disease, is characterized neuropathologically by the presence of amyloid beta (Ab) plaques and tangles made of hyperphosphorylated and misfolded tau, as well gross neuron and synapse loss in affected areas
We show by multiple systems in post-mortem tissue that an apolipoprotein epsilon 4 isoform (APOE4) genotype affects the concentration of clusterin in the synapse and but not in the brain homogenate overall
This increase in clusterin is found to coincide with an increase in the amount of Ab in the same synapses

Summary

Introduction

Alzheimer’s disease, a devastating neurodegenerative disease, is characterized neuropathologically by the presence of amyloid beta (Ab) plaques and tangles made of hyperphosphorylated and misfolded tau, as well gross neuron and synapse loss in affected areas. Of these hallmarks, it is synapse loss that correlates most strongly with the cognitive decline experienced by people living with Alzheimer’s disease (Spires-Jones and Hyman, 2014).

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