Alzheimer’s disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assesses neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.

No description available.

Eine Gemeinsamkeit verschiedener neurodegenerativer Erkrankungen ist die abnormale Ansammlung von Proteinen im Gehirn, wie z. B. von alpha-Synuclein (Syn)-Aggregaten bei der Parkinson''schen Krankheit (PD) oder von Huntingtin (Htt)-Aggregaten bei Chorea Huntington (HD). Am Anfang dieser Studie wurde eine Bibliothek von ca. 5000 natürlichen Substanzen nach Inhibitoren der Htt-Aggregation durchsucht. Eine der wirksamen Substanzen war (-)-Epigallocatechingallat (EGCG), eine Verbindung, die in grünem und schwarzem Tee vorkommt. Die antioxidativen Eigenschaften von EGCG wurden bereits mit einer neuroprotektiven Wirkung in Verbindung gebracht, was EGCG zu einem vielversprechenden Kandidaten für die Entwicklung einer neuen Behandlungsmethode macht. Eine inhibierende Wirkung auf Proteinaggregation wurde jedoch bis jetzt noch nicht nachgewiesen. Diese Studie zeigt, dass EGCG die Aggregation von Htt und Syn hemmt, indem es dosisabhängig eine oligomere Proteinkonformation stabilisiert. Diese Oligomere wirken jedoch nicht als Keime in Aggregationsreaktionen. Zusätzlich verändert EGCG die Exposition bestimmter Epitope, die von konformationsspezifischen Antikörpern im Laufe der Aggregation erkannt werden. Daher könnte die Substanz Proteine, die zur Aggregation neigen, auf einen alternativen Faltungspfad in der Missfaltungskaskade führen. Weiterhin legen die Ergebnisse nahe, dass eine direkte Wechselwirkung zwischen EGCG und Proteinen in einer ungefalteten Konformation stattfindet. In verschiedenen Zellkultur-Modellsystemen verringerte EGCG die Toxizität, die von missgefalteten Proteinen ausgeht, was nahelegt, dass die neu geformten oligomeren Spezies nicht toxisch sind. EGCG könnte daher ein chemisches Chaperon darstellen, das die Missfaltung und Toxizität von Proteinen, die mit neurodegenerativen Krankheiten assoziiert sind, verringert. Die Substanz könnte daher die Basis zur Entwicklung einer neuen Therapie für diese unheilbaren Krankheiten darstellen. / A common feature of neurodegenerative disorders is the abnormal accumulation of aggregated protein the brain, such as alpha-Synuclein (Syn) aggregates in Parkinson''s disease (PD) and Huntingtin (Htt) aggregates in Huntington''s disease (HD). In this study, a library of approximately 5000 natural compounds was screened for inhibitors of Htt aggregation. One of the hits was (-)- Epigallocatechin gallate (EGCG), a compound present in green and black tea. The antioxidant properties of this substance have been linked to neuroprotection before, making it a promising candidate for the development of a treatment for neurodegenerative diseases. Inhibition of protein aggregation by EGCG, however, has not been demonstrated so far. This study shows that EGCG inhibits the aggregation of Htt and Syn by stabilizing an oligomeric conformation of the respective proteins in a dose-dependent manner. These oligomers do not seed the aggregation of Htt and Syn. Also, EGCG modifies the exposure of different epitopes recognized by conformation-specific antibodies during the aggregation process. The compound might therefore lead aggregation-prone proteins on an alternative folding pathway in the misfolding cascade. The results furthermore suggest that direct interaction occurs between EGCG and proteins in an unfolded conformation. EGCG also reduces toxicity caused by misfolded Htt or Syn in cell culture model systems, suggesting that the oligomeric protein species formed in the presence of EGCG are not toxic to living cells. EGCG might therefore represent a chemical chaperone that can modulate misfolding and toxicity of proteins associated with neurodegenerative diseases and could provide the basis for the development of a novel pharmacotherapy for these fatal disorders.

Alzheimer’s disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assesses neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.

Background: Parkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. Objective: This study tested methods to assess usability and determined prerequisites for successful use in patients with PD. - Methods: We performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). - Results: In this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and bettermotor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. Conclusions: eHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.

Chorea Huntington (HD) ist eine neurodegenerative Erkrankung, die durch Ablagerungen von N-terminal Polyglutamin-reichen Huntingtin (Htt) -Fragmenten in den betroffenen Neuronen charakterisiert ist. Das mutierte Htt (mHtt) Protein wird ubiquitär exprimiert. Das zellspezifische Absterben von „medium-sized spiny neurons“ (MSN) wird jedoch im Striatum von HD Patienten verursacht (Albin, 1995). Es wird angenommen, dass Striatum-spezifische Proteine, die mit Htt interagieren, eine wichtige Rolle in der Pathogenese von HD spielen (Ross, 1995). Protein-Protein-Interaktionsstudien haben gezeigt, dass einige der Htt-Interaktionspartner mit unlöslichen Htt-Ablagerungen in den Gehirnen von HD-Patienten kolokalisieren und die Bildung von Protein-Aggregaten beeinflussen (Goehler, 2004). Kürzlich wurde durch die Integration von Genexpressions- und Interaktionsdaten ein Striatum-spezifisches Protein-Interaktionsnetzwerk erstellt (Chaurasia, unveröffentlichte Daten). Eines der identifizierten Proteine ist CRMP1 (collapsin response mediator protein 1), das spezifisch in Neuronen exprimiert wird und möglicherweise eine wichtige Rolle bei der Pathogenese von HD spielt. Experimentelle Untersuchungen mithilfe eines Filter-Retardationsassays zeigten, dass CRMP1 die Anordnung von Htt zu fibrillären, SDS-unlöslichen Aggregaten verringert. Durch Rasterkraftmikroskopie wurde der direkte Effekt von CRMP1 auf den Aggregationsprozess von Htt bestätigt. Ko-Immunopräzipitationsstudien zeigten, dass CRMP1 und Htt in Säugerzellen unter physiologischen Bedingungen miteinander interagieren. Es wurde nachgewiesen, dass CRMP1 die Polyglutamin-abhängige Aggregation und Toxizität von Htt in Zell- und Drosophila-Modellen von HD moduliert. Außerdem konnte CRMP1 in neuronalen Ablagerungen in R6/2 Mäusegehirnen und dessen selektive Spaltung durch Calpaine gezeigt werden. Diese Ergebnisse deuten darauf hin, dass die Lokalisation und Funktion von CRMP1 bei der Krankheitsentstehung verändert werden. / Huntington’s disease (HD) is a neurodegenerative disorder characterized by the accumulation of N-terminal polyglutamine (polyQ)-containing huntingtin (Htt) fragments in affected neurons. The mutant Htt (mHtt) protein is ubiquitously expressed but causes specific dysfunction and death of striatal medium-sized spiny neurons (MSNs) (Albin, 1995). It is assumed that striatum specific proteins interacting with Htt might play an important role in HD pathogenesis (Ross, 1995). Previous protein-protein interaction (PPI) studies demonstrated that many Htt-interacting proteins colocalize with insoluble Htt inclusions in HD brains and modulate the mHtt phenotype (Goehler 2004). A striatum-specific, dysregulated PPI network has been created recently by integrating PPI networks with information from gene expression profiling data (Chaurasia, unpublished data). One of the identified dysregulated proteins potentially involved in HD pathogenesis was the neuron-specific collapsin response-mediator protein 1 (CRMP1). Here, I show that CRMP1 reduces the self-assembly of SDS-insoluble mHtt protein aggregates in vitro, indicating a direct role of CRMP1 on the mHtt aggregation process. Coimmunoprecipitation studies showed that CRMP1 and Htt associate in mammalian cells under physiological conditions. In addition, CRMP1 localizes to abnormal neuronal inclusions and efficiently modulates polyQ-mediated Htt aggregation and toxicity in cell and Drosophila models of HD. This suggests that dysfunction of the protein is crucial for disease pathogenesis. Finally, I observed that CRMP1 localizes to neuronal inclusions and is selectively cleaved by calpains in R6/2 mouse brains, indicating that its distribution and function are altered in pathogenesis. In conclusion, this study presents new findings on the function of CRMP1 and its role in the pathogenesis of HD. The protein interacts with Htt and modulates its aggregation and toxicity, in this way influencing the molecular course of the disease.

No description available.