The fibrillization of α-synuclein (α-syn) is a key event in the pathogenesis of α-synucleinopathies. Mutant α-syn (A53T, A30P, or E46K), each linked to familial Parkinson's disease, has altered aggregation properties, fibril morphologies, and fibrillization kinetics. Besides α-syn, Lewy bodies also contain several associated proteins including small heat shock proteins (sHsps). Since α-syn accumulates intracellularly, molecular chaperones like sHsps may regulate α-syn folding and aggregation. Therefore, we investigated if the sHsps αB-crystallin, Hsp27, Hsp20, HspB8, and HspB2B3 bind to α-syn and affect α-syn aggregation. We demonstrate that all sHsps bind to the various α-syns, although the binding kinetics suggests a weak and transient interaction only. Despite this transient interaction, the various sHsps inhibited mature α-syn fibril formation as shown by a Thioflavin T assay and atomic force microscopy. Interestingly, HspB8 was the most potent sHsp in inhibiting mature fibril formation of both wild-type and mutant α-syn. In conclusion, sHsps may regulate α-syn aggregation and, therefore, optimization of the interaction between sHsps and α-syn may be an interesting target for therapeutic intervention in the pathogenesis of α-synucleinopathies.

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Amyloid-β protein (Aβ) accumulation is one of the major hallmarks of Alzheimer's disease and plays a crucial role in its pathogenesis. Aβ aggregates into fibrils, but rather than these end-products of the aggregation process, intermediate species, referred to as oligomers, have been identified as the most neurotoxic Aβ aggregates. To characterize the different Aβ species and to study the aggregation process, a wide range of techniques has been applied over the past years. These techniques aim to visualize the different Aβ species and study their structure, to separate them, and to quantify the aggregated Aβ forms by immunology-based methods. In this review, we provide an overview and discussion of the most important techniques used for these aims. Often a combination of techniques will be appropriate to obtain the most optimal information.

Despite the limited diagnostic potential of Aβ-oligomer levels in CSF to differentiate between patient groups, and between MCI-AD and MCI-stable patients, changes in CSF Aβ-oligomer levels were related to cognitive decline. Therefore, CSF Aβ-oligomers may aid in the selection of patients with a more aggressive disease course.

Amyloid-b (Ab) is the most prominent protein in Alzheimer's disease (AD) senile plaques. In addition, Ab interacts with a variety of Ab-associated proteins (AAPs), some of which can form complexes with Ab and influence its clearance, aggregation or toxicity. Identification of novel AAPs may shed new light on the pathophysiology of AD and the metabolic fate of Ab. In this study, we aimed to identify new AAPs by searching for proteins that may form soluble complexes with Ab in CSF, using a proteomics approach. We identified the secreted Wnt pathway protein Dickkopf-related protein 3 (Dkk-3) as a potential Abassociated protein. Using immunohistochemistry on human AD brain tissue, we observed that (i) Dkk-3 co-localizes with Ab in the brain, both in diffuse and classic plaques. (ii) Dkk-3 is expressed in neurons and in blood vessel walls in the brain and (iii) is secreted by leptomeningeal smooth muscle cells in vitro. Finally, measurements using ELISA revealed that (iv) Dkk-3 protein is abundantly present in both cerebrospinal fluid and serum, but its levels are similar in non-demented controls and patients with AD, Lewy body dementia, and frontotemporal dementia. Our study demonstrates that Dkk-3 is a hitherto unidentified Ab-associated protein which, given its relatively high cerebral concentrations and co-localization with Ab, is potentially involved in AD pathology.

Amyloid-β (Aβ) is known as the most prominent core protein in Alzheimer's Disease (AD) senile plaques. Although research has focused mainly on Aβ40 and Aβ42 as potential cerebrospinal fluid (CSF) biomarkers, a range of Aβ peptides with variable lengths has been demonstrated in the brains and CSF of AD patients. Recently, it has been found that the Aβ43 peptide may be more abundant than previously assumed, could therefore play an important role in AD pathophysiology, and hence also function as putative biomarker. In this study the value of CSF Aβ43 in AD diagnosis was investigated. Aβ43 levels in CSF were highly correlated with Aβ42 levels. Furthermore, in differentiation of AD from nondemented controls and from patients with Lewy body dementia and frontotemporal dementia, Aβ43 had an equal diagnostic value as Aβ42, both as a single biomarker and in combination with total and phosphorylated tau. In conclusion, quantification of Aβ43 in CSF does not add novel diagnostic information to the differential diagnosis of AD compared to existing biomarkers.

No abstract

Cognitive scientists often use probabilistic equations to model human behavior in ambiguous situations. How, where, and even if such probabilities are represented in the human brain remains largely unknown. Here, we manipulated the probability of simple bottle-pouring action based on two considerations, the relative fullness of two glasses and the relative distance between the two glasses and the bottle. Whole brain functional magnetic resonance imaging was used to measure brain activity while participants viewed probable and improbable pouring actions. Improbable actions elicited increased activity in the theory of mind (ToM) network, commonly found active when trying to grasp the intentions of others, whereas probable actions elicited increased activity in the human mirror neuron system (hMNS) and areas associated with mental imagery and memory. These data provide novel insight into the brain mechanisms humans use to distinguish between high and low-probability actions.