The immunomodulatory receptor Siglec-3/CD33 influences risk for late-onset Alzheimers disease (LOAD), an apparently human-specific post-reproductive disease. CD33 generates two splice variants: a full-length CD33M transcript produced primarily by the LOAD-risk allele and a shorter CD33m isoform lacking the sialic acid-binding domain, produced primarily from the LOAD-protective allele. A SNP that modulates CD33 splicing to favor CD33m is associated with enhanced microglial activity. Individuals expressing more protective isoform accumulate less brain Beta-amyloid and have a lower LOAD risk. How the CD33m isoform increases Beta-amyloid; clearance remains unknown. We report that the protection by the CD33m isoform may not be conferred by what it does, but rather from what it cannot do. Analysis of blood neutrophils and monocytes and a microglial cell line revealed that unlike CD33M, the CD33m isoform does not localize to cell surfaces; instead, it accumulates in peroxisomes. Cell stimulation and activation did not mobilize CD33m to the surface. Thus, the CD33m isoform may neither interact directly with amyloid plaques nor engage in cell-surface signaling. Rather, production and localization of CD33m in peroxisomes is a way of diminishing the amount of CD33M and enhancing Beta-amyloid clearance. We confirmed intracellular localization by generating a CD33m-specific monoclonal antibody. Of note, CD33 is the only Siglec with a peroxisome-targeting sequence, and this motif emerged by convergent evolution in toothed whales, the only other mammals with a prolonged post-reproductive lifespan. The CD33 allele that protects post-reproductive individuals from LOAD may have evolved by adaptive loss-of-function, an example of the less-is-more hypothesis.
from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vKAEv4
via IFTTT
Εγγραφή σε:
Σχόλια ανάρτησης (Atom)
Δημοφιλείς αναρτήσεις
-
Publication date: Available online 4 January 2018 Source: European Journal of Radiology Author(s): Peiyao Zhang, Jing Wang, Qin Xu, Zhen...
-
Publication date: March 2017 Source: Free Radical Biology and Medicine, Volume 104 from #AlexandrosSfakianakis via Alexandros G.Sfak...
-
Dtsch med Wochenschr DOI: 10.1055/s-0043-100054 Hintergrund und Fragestellung Ein etablierter Weg, die optimale Behandlung von Tumorpatien...
-
Background Hyperthyroidism is associated with increased thrombotic risk. As contact system activation through formation of neutrophil extrac...
-
Editors' Recognition for Reviewing in 2020 No abstract available Establishing Satellite Lung Cancer Screening Sites With Telehealth to A...
-
Deepak Thapa, Vanita Ahuja, Deepanshu Dhiman Indian Journal of Anaesthesia 2017 61(12):1012-1014 from #AlexandrosSfakianakis via Alexa...
-
Abstract Limited memory size is considered as a major bottleneck in data centers for intelligent urban computing. It is shown that there e...
-
ecancer is supporting #BowelCancerAwarenessMonth https://t.co/opXxCAAxzE from #AlexandrosSfakianakis via Alexandros G.Sfakianakis on Inore...
-
Abstract Silvicultural models are often developed and applied without due consideration of fire modelling. Yet, this information is import...
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου