Background: We aimed to investigate the influence of oligomeric forms of β-amyloid (Aβ) and the influence of the duration of exposure on the development of tau ph

/pdf/amyloid-oligomers-exacerbate-tau-pathology-in-a-mouse-model-3oe5hcjtk3.pdf

Amyloid Oligomers Exacerbate Tau Pathology in a Mouse Model of Tauopathy

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

Amyloid-Β (AΒ) is the major protein component of neuritic plaques found in Alzheimer's disease. Evidence suggests that the physical aggregation state of AΒ directly influences neurotoxicity and specific cellular biochemical events. Atomic force microscopy (AFM) is used to investigate the three-dimensional structure of aggregated AΒ and characterize aggregate/fibril size, structure, and distribution. Aggregates are characterized by fibril length and packing densities. The packing densities correspond to the differential thickness of fiber aggregates along az axis (fiber height above thex-y imaging surface). Densely packed aggregates (≥100 nm thick) were observed. At the edges of these densely packed regions and in dispersed regions, three types of AΒ fibrils were observed. These were classified by fibril thickness into three size ranges: 2–3 nm thick, 4–6 nm thick, and 8–12 nm thick. Some of the two thicker classes of fibrils exhibited pronounced axial periodicity. Substructural features observed included fibril branching or annealing and a height periodicity which varied with fibril thickness. When identical samples were visualized with AFM and electron microscopy (EM) the thicker fibrils (4–6 nm and 8–12 nm thick) had similar morphology. In comparison, the densely packed regions of ∼≥100 nm thickness observed by AFM were difficult to resolve by EM. The small, 2- to 3-nm-thick, fibrils were not observed by EM even though they were routinely imaged by AFM. These studies demonstrate that AFM imaging of AΒ fibrils can, for the first time, resolve nanometer-scale,z-axis, surface-height (thickness) fibril features. Concurrentx-y surface scans of fibrils reveal the surface submicrometer structure and organization of aggregated AΒ. Thus, when AFM imaging of AΒ is combined with, and correlated to, careful studies of cellular AΒ toxicity it may be possible to relate certain AΒ structural features to cellular neurotoxicity.

The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy

beta/A4 peptides are known to induce neurodegeneration in cultures of rat brain cells and rat neural cell lines (Yankner et al: Science 250:279-282, 1990; Behl et al: Biochem Biophys Res Commun 186:944-950, 1992). The current data show that these peptides induce similar neurodegeneration in SH-SY5Y neuroblastoma cells, extending characterization of beta/A4 toxicity to a human nerve cell line. Human SH-SY5Y cells respond to aggregated beta/A4 with changes in cell shape, membrane blebbing, antigenic modification, loss of attachment to the substrate, and cell death. beta/A4 peptides require aggregation for maximum toxic effects, as cellular degeneration is evoked by aggregated beta/A4 1-42 and 4-41 cysteine but not by monomeric beta/A4 1-40. Aged (pre-aggregated) beta/A4 1-40 also evoked neurodegeneration. Antigenic changes comprise upregulation of Alzheimer's-type tau epitopes, recognized by the PHF-1 and Alz-50 monoclonals. These particular changes in tau support the connectivity between this in vitro model and mechanisms leading to neurodegeneration in Alzheimer's disease. A significant feature of the SH-SY5Y response is that cells must be differentiated before they become sensitive to the degeneration evoked by beta/A4. Signaling pathways leading to beta/A4-evoked neurodegeneration thus are under experimental control, becoming complete only when proliferating cells withdraw from the cell cycle and develop a postmitotic phenotype.

β/A4-evoked degeneration of differentiated SH-SY5Y human neuroblastoma cells

Interaction of beta-amyloid peptides with integrins in a human nerve cell line

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

The nanometer-scale structure of amyloid-beta visualized by atomic force microscopy

β/A4-evoked degeneration of differentiated SH-SY5Y human neuroblastoma cells

Interaction of beta-amyloid peptides with integrins in a human nerve cell line