Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction

Abstract

Recent evidence has suggested a role for soluble oligomeric Aβ species in the pathology of Alzheime's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble Aβ correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of Aβ oligomers: prefibrillar oligomers that are kinetic intermediates in fibril assembly reactions and are specifically recognized by A11 antibody and fibrillar oligomers that may represent fibril seeds or small pieces of fibrils and are recognized by a fibril specific antibody, OC. We have examined the levels of these two types of oligomers in the PBS soluble fraction of brain tissue from control cases, cases with senile degenerative changes (SDC) and AD patients. We found that the levels of soluble fibrillar oligomers detected by OC antibody are significantly elevated in multiple brain regions of AD patients. The elevated fibrillar oligomer levels were found not to be an artifact of tissue homogenization, nor a result of increased Aβ or APP levels. The concentration of fibrillar oligomers in adjacent brain regions of the same patient can vary widely and were not detected in post mortem cerebrospinal fluid. In contrast, the level of prefibrillar oligomers are variable in both AD and age matched controls, indicating that they are not correlated with cognitive dysfunction and suggesting that they precede dementia in AD. Significant correlations were found between the levels of fibrillar oligomers and cognitive decline (MMSE scores) as well as the neuropathological hallmarks of AD. These results indicate that fibrillar oligomers may play a key role in the pathology of AD and may be a new target for diagnostic and therapeutic development.

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

“…In this case, a sharp point is also drawn out from the target membrane, as is observed with short β 2 m amyloid fibrils, but instead of destroying the liposome, the destabilized, extruded membrane region is fused to the viral membrane. The cryoelectron tomography images of β 2 m fibril-membrane interactions presented here suggest that the cellular dysfunction associated with these and other fibrils or fibril-like assemblies (16)(17)(18)(19)(20)(21)27) involves direct bilayer disruption. This membrane damage might arise by direct interaction with the fibril ends and/ or by the creation of new, toxic species by reaction of the fibril ends with the lipids.…”

“…In other cases, toxicity may reside with the amyloid fibrils themselves. Evidence that toxicity correlates with fibrillar assemblies has been reported for yeast and mammalian prion proteins (16,17), human lysozyme (18), Huntingtin exon 1, α-synuclein (19), and Amyloid-β (Aβ) (20,21). Furthermore, Aβ plaques have been shown to form rapidly in vivo and to precede neuropathological changes in a mouse model (22).…”

Levels of Soluble Apolipoprotein E/Amyloid-β (Aβ) Complex Are Reduced and Oligomeric Aβ Increased with APOE4 and Alzheimer Disease in a Transgenic Mouse Model and Human Samples*

“…Soluble oA␤ assemblies are neurotoxic in vitro and in vivo (61), and both soluble A␤ and oA␤ correlate with disease progression in AD patients (62)(63)(64)(65). We previously demonstrated that soluble levels of total A␤42 and oA␤ were increased in E4FAD transgenic mice compared with E2FAD and E3FAD, although the levels of apoE were comparable, suggesting a functional difference between the isoforms.…”

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…Recent evidence suggests that this toxicity may be linked to the aggregation state of the peptide, implicating oligomers, rather than insoluble fibrils, as the primary toxic species [5,6]. While both are found in the brains of postmortem AD patients, soluble A␤ oligomers are better correlated with disease severity than are the classic amyloid plaques containing insoluble A␤ fibrillar deposits [7][8][9]. Furthermore, oligomers are found both extracellularly and intracellularly, and are capable of moving between the interior of the cell and the extracellular space [10,11].…”