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

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.

Figure 1

Schematic representation of Aβ processing and aggregation. (A) Primary sequence of human Aß1-42 with examples of natural or designed intra-Aß mutations (above sequence) and post-translational modifications (below sequence). (B) Amyloid precursor protein (APP) cleavage by β- and γ- secretases releases aggregation-prone Aβ peptides, particularly Aβ1-42. Intra-Aβ mutations and post-translational modifications increase Aβ ability to aggregate even more. It has been suggested that diffusible Aβ aggregates rather than monomer form or fibrils are the synaptotoxic species. These aggregates include ADDLS (Aß-derived diffusible ligands), globulomers (globule-like 12-mers), Aß*56 (56 kDa Aß-containing aggregates derived from brain), protofibrils (soluble, short fibril-shaped often “worm-like” structures) and annular protofibrils (protofibrils that can form pores in membranes). Other aggregation-prone proteins also form synaptotoxic soluble species that may share conformation recognized by antibodies.

Figure 2

Aβ1-42 oligomers prepared from a precursor isopeptide by direct dissolution in physiological buffer [50 ]inhibits long-term potentiation in the hippocampus in vivo. Animals were injected with either vehicle (open circles) or Aβ1-42 (2.5 μg, closed circles) by intracerbroventricular injection (asterisk) 10 min before the conditioning high frequency stimulation (HFS, arrow) in the CA1 area of the anaesthetized rat hippocampus. Values are the mean ± SEM baseline field EPSP (fEPSP) (n = 6-7 per group).

Figure 3

Aβ in soluble extracts of Alzheimer’s disease brain inhibits LTP in vivo. Representative example of LTP impairment after intracerebroventricular (i.c.v.) injection (asterisk) of Tris-buffered saline (TBS) extract of an AD brain containing Aβ (130 pg in total) (closed circles). In vehicle-injected controls, HFS (arrow) induces stable LTP (open circles) in the CA1 area of the anaesthetized rat.

Figure 4

The aggregation-prone prion protein fragment PrP106-126 inhibits LTP in vivo. Animals were injected with either vehicle (open circles) or PrP106-126 (96 ng, closed circles) by i.c.v. injection (asterisk) 10 min before the HFS (arrow) in the CA1 area of the anaesthetized rat hippocampus. Values are the mean ± SEM baseline fEPSP (n = 10 per group).