Alzheimer’s disease Aβ assemblies mediating rapid disruption of synaptic plasticity and memory

Igor Klyubin,William K Cullen,Neng-Wei Hu,Michael J Rowan

doi:10.1186/1756-6606-5-25

Abstract

Alzheimer’s disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, pre-dementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-ß protein (Aβ) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Aβ, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Aβ aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxic amyloidogenic proteins including tau, α-synuclein and prion protein.

Highlights

Many different amyloidogenic proteins form water insoluble deposits in the brains of patients who die from neurodegenerative diseases [1,2,3]
In the light of the many recent reviews of the cellular mechanisms [12,13,14,15,16], the present review focuses on defining the roles of different Aβ assemblies [17,18] in Aβ-mediated synaptic and memory disruption
Since cognitive status in patients with Alzheimer’s disease (AD) is much more strongly correlated with brain concentration of water soluble Aβ rather than insoluble fibrillar Aβ-containing plaque load [19,20], most recent research has focused on soluble species of Aβ

Summary

Introduction

Many different amyloidogenic proteins form water insoluble deposits in the brains of patients who die from neurodegenerative diseases [1,2,3]. I.c.vinjection of PrP106-126 inhibits LTP of synaptic transmission in the CA1 area of the hippocampus in vivo (Cullen et al, unpublished observations) (Figure 4) Another amyloidogenic peptide, ADan, is found deposited in the brains of patients with familial Danish dementia, a rare autosomal dominant form of cognitive impairment with AD-like neuropathology. Antibodies that bind PrPC within the region of 93-109 [105] or 93-102 [107] prevented the inhibition of hippocampal LTP by synthetic Aβ1-42 oligomers in vitro Consistent with these reports, the in vivo synaptic plasticity disrupting actions of AD brain extracts containing water soluble Aβ were dependent on PrPC [67]. It will be important to determine if the fact that different APP transgenic mice at different ages express different potentially synaptotoxic Aβ assemblies [18,120] can help explain this controversy

Conclusion

31. Lynch MA

37. Hard T

78. Glabe CG

93. Vassallo N

96. Mallucci GR