"Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-β fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-β, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein.

Myelin dysfunction drives amyloid-β deposition in models of Alzheimer's disease.

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation. As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.

A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimer's Disease Mouse Model.

A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer's disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD.

Combined long-term enriched environment and caffeine supplementation improve memory function in C57Bl6 mice.

Regular physical activity has been associated with healthy brain aging, reflected by beneficial effects on cognition and learning and memory. Nutritional supplements such as caffeine have been shown to act as cognitive enhancers and may possess neuroprotective properties. Interestingly, caffeine also improves athletic capabilities and is widely used by athletes because of its performance-enhancing effect, while information on potential additive beneficial effects of physical activity and caffeine on cognitive performance is scarce.

Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.

β-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the major described β-secretase to generate Aβ peptides in Alzheimer's disease (AD). However, all therapeutic attempts to block BACE1 activity and to improve AD symptoms have so far failed. A potential candidate for alternative Aβ peptides generation is the metalloproteinase meprin β, which cleaves APP predominantly at alanine in p2 and in this study we can detect an increased meprin β expression in AD brain.