Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models

Abstract

Many proteins suspected of causing neurodegenerative diseases exist in diverse assembly states. For most, it is unclear whether shifts from one state to another would be helpful or harmful. We used mutagenesis to change the assembly state of Alzheimer disease (AD)-associated amyloid-␤ (A␤) peptides. In vitro, the "Arctic" mutation (A␤E22G) accelerated A␤ fibrillization but decreased the abundance of nonfibrillar A␤ assemblies, compared with wild-type A␤. In human amyloid precursor protein (hAPP) transgenic mice carrying mutations adjacent to A␤ that increase A␤ production, addition of the Arctic mutation markedly enhanced the formation of neuritic amyloid plaques but reduced the relative abundance of a specific nonfibrillar A␤ assembly (A␤*56). Mice overexpressing Arctic mutant or wildtype A␤ had similar behavioral and neuronal deficits when they were matched for A␤*56 levels but had vastly different plaque loads. Thus, A␤*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar A␤ deposits. Therapeutic interventions that reduce A␤ fibrils at the cost of augmenting nonfibrillar A␤ assemblies could be harmful. Alzheimer disease (AD)3 and many other neurodegenerative disorders are associated with the accumulation of abnormal protein assemblies in the central nervous system (CNS). Much evidence suggests that this association reflects a causal relationship in which the abnormal proteins actually trigger the neuronal dysfunction and degeneration that characterize these conditions (1-3). The prevalence of AD and other neurodegenerative proteinopathies is increasing rapidly around the world, most likely because of their age dependence, the increasing longevity of many populations, and the lack of effective strategies for treatment and prevention (4 -6). This alarming trend underlines the need to better understand the relationship between the accumulation of abnormal proteins in the CNS and the decline of neurological function.This relationship has been difficult to analyze in depth because proteins associated with neurodegenerative disorders can exist in diverse assembly states, and distinct assemblies can differ markedly in pathogenic potential. For example, the amyloid-␤ (A␤) peptide, which seems to play a causal role in AD, can exist as monomers, low molecular weight oligomers (such as dimers and trimers), larger globular oligomers (such as A␤*56, A␤-derived diffusible ligands, amylospheroids, and globulomers), amyloid pores, protofibrils, fibrils, and amyloid plaques that contain densely packed A␤ fibrils and a large number of other molecules and cellular elements (7-15). Which of these structures contributes most critically to neurological decline in AD is a matter of active study and debate that has important implications for therapeutic interventions. Studies of transgenic mice with neuronal expression of human amyloid precursor proteins (hAPP), from which A␤ is released by proteolytic cleavage, suggest that nonfibrillar A␤ assemblies are more critical than amyloid plaques in the pathogene...

Small-molecule conversion of toxic oligomers to nontoxic β-sheet–rich amyloid fibrils

“…Moreover, it needs to be seen whether compound-induced accelerated deposition of A42 aggregates has beneficial effects on disease pathogenesis in AD models. Experimental evidence supporting such a view has been presented previously, indicating that accelerated A fibrillization reduces oligomer levels and functional deficits in AD mouse models 49 . We suggest that compounds like O4, which bind to -sheet-rich amyloid structures might reduce their toxicity by preventing the abnormal interactions of small aggregate species with cellular proteins.…”

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

“…Furthermore, it also remains unclear whether h-αSyn WT can alter Aβ-induced phenotypes, considering the distinct properties of αSyn A30P (54). Second, despite previous evidence reporting the association of Aβ oligomers and cognitive deficits in J20 mice before plaque formation (55), the in vivo results presented here cannot rule out the possibility that the potentiation of the memory impairments seen in J20×TgI2.2 bigenic mice is a result of the overexpression of APP in these mice (i.e., ∼threefold over endogenous APP). However, recent analyses using single-cell qPCR revealed that individual neurons in sporadic AD can harbor an averaged copy number for APP of 3.8-4 (up to 12 copies) over control samples (56), suggesting that the threefold elevation of APP seen in J20 mice might actually be relevant to AD.…”

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

“…2). To identify A␤-42 changes in Tg2576 mice, we used four different antibodies: (1) A␤-42 antibody 6E10, which recognizes all forms (monomers, oligomers, and fibrils) of A␤-42 and a great variety of APP metabolites (Cheng et al, 2007); (2) A␤-42 antibody A11, which recognizes A␤-42 oligomers and other oligomers, such as ␣-synuclein (Kayed et al, 2003); (3) APP antibody (ab15272, Abcam), which recognizes the N-terminal portion of the APP (this antibody does not recognize A␤-42); and (4) ␣-synuclein antibody (Santa Cruz Biotechnology), which recognizes ␣-synuclein.…”