Martin Herbst

EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.

The accumulation of β-sheet–rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinsons and Alzheimers diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (−)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both α-synuclein and amyloid-β by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of β-sheet–rich amyloid, the formation of unstructured, nontoxic α-synuclein and amyloid-β oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.

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

Several lines of evidence indicate that prefibrillar assemblies of amyloid-β (Aβ) polypeptides, such as soluble oligomers or protofibrils, rather than mature, end-stage amyloid fibrils cause neuronal dysfunction and memory impairment in Alzheimers disease. These findings suggest that reducing the prevalence of transient intermediates by small molecule-mediated stimulation of amyloid polymerization might decrease toxicity. Here we demonstrate the acceleration of Aβ fibrillogenesis through the action of the orcein-related small molecule O4, which directly binds to hydrophobic amino acid residues in Aβ peptides and stabilizes the self-assembly of seeding-competent, β-sheet-rich protofibrils and fibrils. Notably, the O4-mediated acceleration of amyloid fibril formation efficiently decreases the concentration of small, toxic Aβ oligomers in complex, heterogeneous aggregation reactions. In addition, O4 treatment suppresses inhibition of long-term potentiation by Aβ oligomers in hippocampal brain slices. These results support the hypothesis that small, diffusible prefibrillar amyloid species rather than mature fibrillar aggregates are toxic for mammalian cells.

Small Molecule Inducers of Heat-Shock Response Reduce polyQ-Mediated Huntingtin Aggregation

Enhancing cellular defense mechanisms against different kinds of stress may be an attractive therapeutic strategy for neurodegenerative diseases. In particular, inducing the expression of molecular chaperones might reduce the formation of misfolded proteins and toxic aggregates that occur in polyglutamine (polyQ) disorders such as Huntington’s disease. Geldanamycin, a natural substance that modulates Hsp90 function, was previously shown to induce a heat-shock response and to reduce polyQ aggregation in mammalian cells. However, because of toxic and unfavorable pharmacokinetic properties, geldanamycin is not suitable for clinical use. In this study we evaluated the effects of the pharmacologically improved geldanamycin derivatives 17-DMAG and 17-AAG on polyQ aggregation in mammalian cells. Quantitative RT-PCR and SDS-PAGE experiments revealed that 17-DMAG induces expression of the molecular chaperones Hsp40, Hsp70, and Hsp105 in mammalian cells and inhibits the formation of mutant huntingtin aggregates with higher efficiency than 17-AAG or geldanamycin itself. Induction of a heat-shock response and inhibition of polyQ aggregation occurred at nanomolar concentrations. We suggest that geldanamycin derivatives such as 17-DMAG should be considered for the development of a drug treatment for polyQ disorders and other neurodegenerative diseases involving protein aggregation.

Therapeutic Approaches to Polyglutamine Diseases: Combating Protein Misfolding and Aggregation

Polyglutamine diseases are autosomal dominant, late-onset neurodegenerative disorders. Expansion of a polyglutamine (polyQ) tract above a threshold size leads to misfolding and aggregation and eventual intracellular accumulation of the disease-specific protein. To date, only symptomatic treatments of limited effectiveness are available. Various research strategies aim to interfere with known steps in the pathomechanism. Protein misfolding and aggregation probably occur very early in the cascade of pathogenic events and are therefore attractive targets for potential drug treatment. Misfolding of polyQ proteins may either be prevented by drugs that stabilize the native conformation or via induction of cellular chaperones. Several amyloid-binding dyes as well as small molecules that inhibit polyQ protein aggregation have been identified in compound screens and may be entered into drug development. Small molecule inhibitors of further pathogenic phenomena like transcriptional repression, excitotoxicity, mitochondrial dysfunction, and neuronal cell death have been tested in vitro and in vivo. The first drugs have now reached clinical trial stage. More general studies of how putative steps in the pathomechanism can be modulated will yield further insights into the pathogenesis of polyQ disorders.

Posttraumatic bilateral hypertrophic olivary degeneration.

Eighteen months prior to admission to our institution, a 22-year-old male sustained a severe traumatic brain injury due to a motocross accident. After regaining consciousness he suffered from right-sided hemiparesis, moderate truncal and limb ataxia. Three months later, he developed postural and action tremor. During rehabilitation, truncal and limb ataxia deteriorated further until he was no longer able to move himself from the wheel chair into the bed without help. On admission the patient presented with a severe cerebellar syndrome (ataxia, postural and intentional tremor, dysdiadochokinesis and dysarthria) as well as a rhythmic palatal myoclonus. Brain MRI performed on admission showed multiple sites of diffuse axonal injury (DAI) at the cortico-medullary junctions and the corpus callosum. Two foci of DAI were found adjacent to the entry of the superior cerebellar peduncle into the midbrain on each side (Fig. 1). Bilaterally, the inferior olivary nucleus was enlarged and showed marked T2 hyperintensity (Fig. 1). The clinical and imaging findings described here are pathognomonic for bilateral hypertrophic olivary degeneration (HOD) secondary to traumatic disruption of fibers in the triangle of Guillain and Mollaret [1]. Dorsal midbrain injuries are well-known sequelae of TBI as the midbrain is translated against the rigid tentorial hiatus [2]. This can cause damage to either the anterior spinocerebellar tract or the cerebellar efferences, which mainly run from the dentate nucleus via the superior cerebellar peduncle to the red nucleus and the thalamus (dentato-rubral tract, dentatothalamic tract), and explains our patient0s marked cerebellar syndrome despite a morphologically intact cerebellum. Furthermore, the dentato-rubral tract constitutes one component of the triangle of Guillain and Mollaret, a functional neuronal network arranged in a feedback loop fashion encompassing the cerebellum including the dentate nucleus, the red nucleus and the inferior olivary nucleus. Fibers run from the dentate nucleus via the dentato-rubral tract within the superior cerebellar peduncle to the contralateral red nucleus. Via the central tegmental tract fibers from the red nucleus project to the inferior olive, and from there olivo-cerebellar fibers run via the inferior cerebellar peduncle to the contralateral cerebellar cortex that projects to the dentate nucleus. Any lesion within this neuronal network, be it neoplastic, ischemic, hemorrhagic or traumatic, can cause HOD and lead to characteristic delayed symptoms, in particular involuntary movements such as myoclonus or rhythmic tremor of palatal and adjacent structures [3]. Whereas neurodegeneration including transsynaptic degeneration usually leads to atrophy of affected structures, subacute and transient neuronal cellular hypertrophy as a consequence of transsynaptic degeneration is a pathogenetic feature unique to the inferior olivary nucleus [4]. Corresponding imaging features follow a characteristic time course with olivary T2 signal elevation within one month and a unique degenerative hypertrophy developing from 6 months to several years following the inciting brain lesion [1]. In later stages, contralateral cerebellar atrophy may be observed and both olivary signal elevation and hypertrophy resolve [1, 5]. E. Siebert (&) Department of Neuroradiology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany e-mail: eberhard.siebert@charite.de

Alzheimer's disease: charting the crossroads between neurology and psychology

Neurodegenerative disorders such as Alzheimers disease (AD) are increasingly recognised to have a long prodromal stage before the onset of symptoms defining the dementia syndrome. This phase may last up to years or even decades. An intensive search has been initiated for signs or symptoms that might enable prediction of dementia development.1 The motivation for identifying such predictors comes from the assumption that disease-modifying treatment might be more effective in early or even presymptomatic stages when the pathogenic mechanisms have not progressed, and irreversible damage to neurons and neural networks is still limited. Therefore, early recognition of imminent dementia may play an important role in the future. In addition, a definition of dementia that focuses on cognitive symptoms might conceal early non-cognitive symptoms. In fact, we have learned from diverse recent studies that dementia is often preceded by depressive symptoms years before the onset of cognitive decline. It remains unclear, however, whether depression actually represents an early disease symptom, a psychological reaction to cognitive deterioration perceived by the affected individual, or whether it is a true risk factor for dementia …