Aβ1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Aβ oligomers (referred to as ADDLs, for Aβ-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer’s disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer’s disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Aβ-derived diffusible ligands acting upon particular neural signal transduction pathways.

https://www.pnas.org/content/pnas/95/11/6448.full.pdf

Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins

Converging lines of evidence suggest that progressive accumulation of the amyloid beta-protein (A beta) plays a central role in the genesis of Alzheimer's disease, but it was long assumed that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. Over the past decade, data have emerged from the use of synthetic A beta peptides, cell culture models, beta-amyloid precursor protein transgenic mice and human brain to suggest that pre-fibrillar, diffusible assemblies of A beta are also deleterious. Although the precise molecular identity of these soluble toxins remains unsettled, accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1471-4159.2006.04426.x

A beta oligomers - a decade of discovery.

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic Aβ peptides. The platelet-derived growth factor β chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral Aβ1–42 levels, whereas an experimental mutation of the β-secretase cleavage site (671M→I) eliminated production of human Aβ. High levels of Aβ1–42 resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with Aβ levels but not with hAPP levels or plaque load. We conclude that Aβ is synaptotoxic even in the absence of plaques and that high levels of Aβ1–42are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent Aβ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

https://www.jneurosci.org/content/jneuro/20/11/4050.full.pdf

High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.

Ordered protein aggregation in the brain is a hallmark of Alzheimer's disease and scrapie. The disease-specific amyloid fibrils comprise primarily a single protein, amyloid beta, in Alzheimer's disease, and the prion protein in scrapie. These proteins can be induced to form aggregates in vitro that are indistinguishable from brain-derived fibrils. Consequently, much effort has been invested in the development of in vitro model systems to study the details of the aggregation processes and the effects of endogenous molecules that have been implicated in disease. Selected studies of this type are reviewed herein. A simple mechanistic model has emerged for both processes that involves a nucleation-dependent polymerization. This mechanism dictates that aggregation is dependent on protein concentration and time. Furthermore, amyloid formation can be seeded by a preformed fibril. The physiological consequences of this mechanism are discussed.

MODELS OF AMYLOID SEEDING IN ALZHEIMER'S DISEASE AND SCRAPIE: Mechanistic Truths and Physiological Consequences of the Time-Dependent Solubility of Amyloid Proteins

Amyloid β-Protein Fibrillogenesis: DETECTION OF A PROTOFIBRILLAR INTERMEDIATE

Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths.

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Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths.