Monomeric amyloid-β reduced amyloid-β oligomer-induced synapse damage in neuronal cultures

Clive Bate,Alun Williams

doi:10.1016/j.nbd.2017.12.007

Clive Bate, Alun Williams

Open Access

https://doi.org/10.1016/j.nbd.2017.12.007

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Abstract

Alzheimer's disease is a progressive neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) in the brain. Aβ oligomers are believed to cause synapse damage resulting in the memory deficits that are characteristic of this disease. Since the loss of synaptic proteins in the brain correlates closely with the degree of dementia in Alzheimer's disease, the process of Aβ-induced synapse damage was investigated in cultured neurons by measuring the loss of synaptic proteins. Soluble Aβ oligomers, derived from Alzheimer's-affected brains, caused the loss of cysteine string protein and synaptophysin from neurons. When applied to synaptosomes Aβ oligomers increased cholesterol concentrations and caused aberrant activation of cytoplasmic phospholipase A2 (cPLA2). In contrast, Aβ monomer preparations did not affect cholesterol concentrations or activate synaptic cPLA2, nor did they damage synapses. The Aβ oligomer-induced aggregation of cellular prion proteins (PrPC) at synapses triggered the activation of cPLA2 that leads to synapse degeneration. Critically, Aβ monomer preparations did not cause the aggregation of PrPC; rather they reduced the Aβ oligomer-induced aggregation of PrPC. The presence of Aβ monomer preparations also inhibited the Aβ oligomer-induced increase in cholesterol concentrations and activation of cPLA2 in synaptosomes and protected neurons against the Aβ oligomer-induced synapse damage. These results support the hypothesis that Aβ monomers are neuroprotective. We hypothesise that synapse damage may result from a pathological Aβ monomer:oligomer ratio rather than the total concentrations of Aβ within the brain.

Highlights

Alzheimer's disease (AD) is a complex neurological disorder characterized by a progressive dementia resulting from synapse failure (Selkoe, 2002; Tanzi, 2005)
Since the loss of synapses and synaptic proteins is a feature of AD that strongly correlates with cognitive decline in AD (Counts et al, 2006; Masliah et al, 1991; Reddy et al, 2005) synapse density was measured by determining the amounts of synaptophysin and cysteine string protein (CSP) in cultured neurons (Lipton et al, 2001)
Aβ caused synapse damage in cultured neurons - Since the loss of synaptic proteins is a feature of AD that strongly correlates with cognitive decline (Counts et al, 2006; Masliah et al, 1991; Reddy et al, 2005) the effect of Aβ on the amounts of synaptic proteins in cultured neurons was studied

Summary

Introduction

Alzheimer's disease (AD) is a complex neurological disorder characterized by a progressive dementia resulting from synapse failure (Selkoe, 2002; Tanzi, 2005). The mechanisms of Alzheimer’s-related synapse damage can be examined by incubation of cultured neurons with Aβ. Soluble forms of Aβ derived from the brains Alzheimer’s patients caused synapse degeneration in neurons (Yang et al, 2017). The biological effects of these Aβ oligomers occurred at picomolar concentrations, similar concentrations to those found in the cerebrospinal fluid of Alzheimer’s patients (Bibl et al, 2007; McLean et al, 1999; Mehta et al, 2000). Confusion may arise due to the heterogeneity of Aβ in monomer preparations, in addition to Aβ40 and Aβ42 peptides there are other APP fragments in cerebrospinal fluid (Brinkmalm et al, 2012) and that some of these carboxy-terminal fragments of APP have biological activity (Willem et al, 2015). In the present study Aβ monomer preparations and Aβ oligomers were isolated from soluble brain extracts and their biological activity studied

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