Biomarkers of Errant Endosome Spotted in Cerebrospinal Fluid
2020年12月5日 · VPS35 is a core component of the retromer complex, a protein machine that helps endosomes recycle cell surface proteins. Retromer-induced traffic jams that cause protein pileups have been implicated in AD pathogenesis (Small et al., 2017; Jun 2012 news). In fact, VPS35 missense mutations have been found in people with AD, and VPS35 levels were ...
ALS/FTD Genes Converge on Endolysosomal System, Stoking TDP …
2022年10月18日 · Crucially, cells expressing poly-GA that had endosome abnormalities also shunted TDP-43 from the nucleus into cytoplasmic inclusions, which are a hallmark pathology of ALS and FTD. These observations are interesting, and the suggestion that poly-GA and TBK1 may be linked to TDP-43 mis-localization places them at the heart of pathogenesis.
Without SORL1, Endosomes Swell in Neurons but not Microglia
2020年6月2日 · This happened only in neurons, not microglia. The SORL1 knockout recapitulates one of the earliest cytopathological hallmarks of AD, Young told Alzforum. Perhaps counterintuitively, a β-secretase inhibitor didn’t keep the organelles from swelling. “We show that removal of SORL1 causes enlargement of endosomes independently of APP ...
Familial AD Mutations, β-CTF, Spell Trouble for Endosomes
2019年8月17日 · Endosome enlargement is an early cytopathology in AD, and multiple genes that confer increased risk for sporadic AD (sAD) are in loci attributed to endocytosis and vesicular trafficking. Understanding this pathway and how it becomes dysfunctional in central nervous system cells is imperative, as aberrant vesicular trafficking is a common theme ...
When SORL1 Dimerizes in Endosomes, Retromers Recycle APP Faster
2023年2月2日 · Still, he interprets the findings as clear evidence of the intimate collaboration between SORL1 and retromer in driving endosomal recycling, and suggests that SORL1 dimerization is a critical mechanistic step of this pathway. Moreover, Andersen emphasized that SORL1 cargo proteins, including APP, glutamate receptors, and TREKB, also form ...
Catch and Release: Cryo-EM Reveals How LRP2 Receptor
2023年2月10日 · In the acidic environs of the endosome, the homodimers ball up, retracting their ligand binding sites and brushing off cargo. The authors propose that these pH-driven acrobatics drive LRP2’s catch and release of ligands, such as apolipoproteins, Aβ, and tau. Other members of this large receptor family might work the same way.
APP C-Terminal Fragments Stifle Calcium Flow from ER to Lysosomes
2024年4月27日 · This paper by Bretou et al. is a tour de force with diverse and elegant methods, and provides numerous novel insights, such as on the importance of APP CTFs at membrane contact sites between the ER and late endosome/lysosomes (LE/Lys) relating to γ-secretase inhibition/loss of presenilins and lysosomal calcium. It is also remarkable that ...
Alzheimer's-related endosome dysfunction in Down syndrome is …
2010年1月26日 · News: APP in Pieces: βCTF implicated in Endosome Dysfunction It is established that overexpression of APP, such as in Down syndrome, leads to endosome dysfunction. The article by Jiang et al. (1) now elegantly shows that the endosomal abnormalities are not caused by increased levels of Aβ.
A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC
2019年9月3日 · Endosome enlargement is an early cytopathology in AD, and multiple genes that confer increased risk for sporadic AD (sAD) are in loci attributed to endocytosis and vesicular trafficking. Understanding this pathway and how it becomes dysfunctional in central nervous system cells is imperative, as aberrant vesicular trafficking is a common theme ...
SORL1 is a receptor for tau that promotes tau seeding. - ALZFORUM
2024年5月6日 · This paper by J.M. Cooper et al. is a well-executed study that advances our thinking about the route tau travels once internalized. In essence, the problem we face is that, internalized via LRP1 through which it enters endosomes, tau must escape the endosome before it assembles into cytoplasmic neurofibrillary tangles.