Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

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...

Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-β aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-β in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-β aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-β aggregates, including soluble amyloid-β oligomers. Different soluble amyloid-β oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-β oligomers previously described in mouse models-amyloid-β trimers, Aβ*56 and amyloid-β dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-β trimers appear to be the fundamental amyloid-β assembly unit of Aβ*56 and are present in young mice prior to memory decline, amyloid-β trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. Aβ*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-β dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between Aβ*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between Aβ*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-β dimers or amyloid-β trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-β dimers, but the lowest levels of Aβ*56 and amyloid-β trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults Aβ*56 increased ahead of amyloid-β dimers or amyloid-β trimers, and pathological tau proteins and postsynaptic proteins correlated with Aβ*56, but not amyloid-β dimers or amyloid-β trimers. We propose that Aβ*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.

For nearly 100 years following the first description of this neurological disorder by Dr. Alois Alzheimer, amyloid plaques and neurofibrillary tangles have been hypothesized to cause neuronal loss. With evidence that the extent of insoluble, deposited amyloid poorly correlated with cognitive impairment, research efforts focused on soluble forms of Aβ, also referred as Aβ oligomers. Following a decade of studies, soluble oligomeric forms of Aβ are now believed to induce the deleterious cascade(s) involved in the pathophysiology of Alzheimer’s disease. In this review, we will discuss our current understanding about endogenous oligomeric Aβ production, their relative toxicity in vivo and in vitro, and explore the potential future directions needed for the field.