Progressive accumulation of amyloid‐β oligomers in Alzheimer’s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins

Abstract

The cognitive impairment in patients with Alzheimer's disease is closely associated with synaptic loss in the neocortex and limbic system. Although the neurotoxic effects of aggregated amyloid-b oligomers in Alzheimer's disease have been studied extensively in experimental models, less is known about the characteristics of these aggregates across the spectrum of Alzheimer's disease. In this study, postmortem frontal cortex samples from controls and patients with Alzheimer's disease were fractionated and analyzed for levels of oligomers and synaptic proteins. We found that the levels of oligomers correlated with the severity of cognitive impairment (blessed information-memory-concentration score and mini-mental state examination) and with the loss of synaptic markers. Reduced levels of the synaptic vesicle protein, vesicle-associated membrane protein-2, and the postsynaptic protein, postsynaptic density-95, correlated with the levels of oligomers in the various fractions analyzed. The strongest associations were found with amyloid-b dimers and pentamers. Co-immunoprecipitation and doublelabeling experiments supported the possibility that amyloid-b and postsynaptic density-95 interact at synaptic sites. Similarly, in transgenic mice expressing high levels of neuronal amyloid precursor protein, amyloid-b co-immunoprecipitated with postsynaptic density-95. This was accompanied by a decrease in the levels of the postsynaptic proteins Shank1 and Shank3 in patients with Alzheimer's disease and in the brains of amyloid precursor protein transgenic mice. In conclusion, this study suggests that the presence of a subpopulation of amyloid-b oligomers in the brains of patients with Alzheimer's disease might be related to alterations in selected synaptic proteins and cognitive impairment.

Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration

“…Numerous controls confirmed that the cytoskeletal changes we report are attributable specifically to human Aβ dimers [the most abundant form of soluble oligomers recoverable from AD cortex (10,11,28)]: (i) monomers from the same size-exclusion chromatography at equal or higher amounts had no effect; (ii) corresponding SEC fractions from age-matched control brains lacking Aβ were negative; (iii) the SDS-stable dimers were recoverable from the media at the end of the treatment, proving they were present throughout the exposures that resulted in alteration of the tau cytoskeleton; (iv) pure, synthetic Aβ dimers produced closely similar effects to AD-brain derived dimers (albeit at much higher concentrations); (v) immunodepletion of natural Aβ dimers from the SEC fractions precluded any subsequent neuritic injury; and (vi) coadministering highly specific monoclonal antibodies to the N terminus but not the C terminus of Aβ prevented the effects.…”

“…Various aggregated forms of synthetic Aβ designated ADDLs (3) or protofibrils (44,45) and generated from high concentrations of a single, defined Aβ peptide, have not been proven to occur as such in the human brain, whereas heterogeneous dimers, trimers (10,11,28), slightly larger low-n oligomers (11), and dodecamers (28) have. Deciphering the mechanisms of these natural oligomers will require purifying them to homogeneity from the AD cortex, labeling them, and exposing primary neurons or brain slices to them to identify in unbiased fashion their molecular targets.…”

“…Importantly, SDS-stable higher oligomers, including dodecamers, were not detectable by IP-SEC in AD-TBS extracts (Fig. 1A); accordingly, we focused on the dimers, cortical levels, of which were recently shown by others to correlate strongly with several features of the AD phenotype (Mini-Mental State Examination score; Blessed cognitive score; Braak score; synaptic protein levels) (11). We prepared primary cultures of hippocampal neurons from E18 rat embryos.…”

Mechanisms and rates of nucleation of amyloid fibrils

“…where ∆F mic refers to the micellation free energy and is simply (5) at N = N h . In order for this N h -size micelle to aggregate into (N − 1)-size, it has to adsorb additional (N − N h − 1) monomers.…”

“…As more evidence emerges that oligomers produced at the early stages of amyloid aggregation could be the most toxic species [5][6][7] , researchers have been keen on understanding the details of the nucleation mechanism of fibrils, in particular, determining the critical nucleus size n c of primary nucleation: the minimum size that enables the extension of amyloid fibrils. Yet, due to the transient nature of critical nuclei and the low concentration of nuclei over the whole aggregation time course, there have been no direct experimental methods of observing amyloid nucleation process 8 .…”