Cholesterol catalyst for amyloid aggregation

A team from the British University of Cambridge has identified a molecular link between cholesterol and amyloid beta aggregation that could explain why cholesterol processing pathways are implicated in Alzheimer's disease (AD) risk by genomewide association studies (GWAS). ApoE4 status is the strongest known genetic risk factor not just for the development of AD, but for any disease. But why it should matter so much has been unclear. The team tested amyloid beta's aggregation speed in vesicles that were either cholesterol-containing or cholesterol-free, and showed that cholesterol acted as a catalyst for amyloid beta aggregation, speeding plaque formation of A-beta 42 by up to 20-fold. The authors wrote that "these results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of A-beta 42 aggregation, thereby helping rationalize the link between Alzheimer's disease and the impairment of cholesterol homeostasis." Their work appeared in the May 7, 2018, online issue of Nature Chemistry.

Cell type (mis-)shapes alpha-synuclein

Alpha-synuclein, when it misfolds and accumulates, can cause several different neurodegenerative disorders, collectively known as the synucleinopathies. Which synucleinopathy develops depends partly on the affected cell type. Now, researchers from the University of Pennsylvania have found alpha-synuclein can also misfold into different shapes, and those shapes also affect disease type. The team compared alpha-synuclein aggregates that form Lewy bodies in neurons, leading to Parkinson's disease and other disorders, with those that form in oligodendrocytes to cause multiple system atrophy (MSA), a very aggressive synucleinopathy. The team showed that the oligodendrocyte form of alpha-synuclein was roughly 1,000-fold more potent at seeding aggregates than Lewy bodies, "consistent with the highly aggressive nature of multiple system atrophy." The team also showed that using neuronal alpha-synuclein to "seed" aggregates in oligodendrocytes led to the development of MSA-type aggregates, "highlighting the fact that distinct alpha-Syn strains are generated by different intracellular milieus." The team published its results in the May 10, 2018, issue of Nature.

'Flesh-eating bacteria' hijack pain, immune response

Streptococcus pyogenes are sometimes called "flesh-eating bacteria." The name is sensationalist, but not undeserved – infection with S. pyogenes can destroy soft tissue, a process known as necrotizing fasciitis, to the point that amputation is necessary, and serious infections are fatal in a quarter to a third of all cases. Researchers at Harvard Medical School have shown that S. pyogenes directly activates pain-sensing neurons, which set off an immunosuppressive response that helps the bacteria survive. In animal experiments, either killing pain-sensing neurons or inhibiting their signaling via botulinum toxin or CGRP antagonists, which are being developed as migraine therapies, improved immune system control of S. pyogenes infection. The researchers concluded that "neurons and their signaling to the immune system have a major impact on the outcome of bacterial soft tissue infection," and that "targeting the peripheral nervous system could provide therapeutic approaches in invasive infections including necrotizing fasciitis." They published their results in the May 10, 2018, online issue of Cell.

You're only as old as your mitochondria feel

Mitochondrial protein synthesis affects general cellular functioning not just directly, but also through general effects on protein synthesis in the cytoplasm. Mitochondria have their own genome, and researchers from the Swedish Stockholm University investigated the effects of either improving or perturbing the mitochondrial quality control center. They found that "decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced... proteostasis transcription program that regulates genes important for mitochondrial proteostasis." The findings suggest that mitochondrial and cytosolic protein synthesis are integrated with stress signaling in the nucleus in "an inter-connected organelle quality control network that determines cellular lifespan." The team's work appeared in the May 8, 2018, online issue of Cell Metabolism.

Microenvironment ages blood stem cells

Autonomic nervous system signaling is important for maintaining the self-renewal capacity of blood-forming stem cells, and the loss of such signaling, which naturally occurs during aging, was one driver of stem cell aging. Stem cells are maintained via multiple mechanisms, both within the cells themselves and in the form of cues from the microenvironment. Blood-forming stem cells live in the bone marrow, and microenvironmental cues from the bone marrow influence their ability to maintain their regenerative capacity. Researchers from the Albert Einstein College of Medicine have shown that the sympathetic nervous system, which releases adrenaline into the bone marrow in a regular circadian rhythm, was important for enabling the bone marrow to maintain stem cells. The team showed that loss of signaling by adrenoceptor beta 3 in the bone marrow of young mice led to premature blood stem cell aging. Conversely, activating adrenoceptor beta 3 in the bone marrow of old mice "significantly rejuvenated the in vivo function" of aged blood stem cells, suggesting a possible therapeutic approach to preserving or repairing blood stem cell function. The team reported its findings in the May 7, 2018, online issue of Nature Medicine.