LRP1 is a neuronal receptor for α-synuclein uptake and spread

In the paper

“Particularly, the oligomeric α-Syn species appear to be prone to uptake and spread from cell-to-cell in a prion-like manner, leading to the templated misfolding of the native forms of α-Syn and formation of α-Syn aggregates throughout the brain, which are the defining pathological features of Parkinson’s disease (PD) and dementia with Lewy body (DLB) [12–19].”

What the sources say

• Partly supported

  In “Grafted cells develop Lewy bodies” (page unavailable), the review reports uptake of α-synuclein oligomers in cultured neurons and seeding of endogenous α-synuclein aggregates. It also suggests that non-native α-synuclein can spread between cells and affect progressively greater parts of the central nervous system in Parkinson’s disease. It does not establish that oligomers specifically drive spread throughout the brain, or address dementia with Lewy bodies as the citing sentence does. (LLM, conf=0.84)

  cites [12] Brundin P, Melki R, Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 2010;11:301–7. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [13] Angot E, Steiner JA, Hansen C, Li JY, Brundin P. Are synucleinopathies prion-like disorders? The Lancet Neurology. 2010;9:1128–38. source
• Partly supported

  In “Does LP retrogradely spread in cPD?” (page not specified), the paper reports oligomeric α-syn spreading through the brainstem in a viral-expression model. It attributes uptake, recruitment of endogenous α-syn into aggregates, and proposed prion-like templating specifically to fibrils, however. It does not establish that oligomers drive that full sequence or produce aggregates throughout the brain. (LLM, conf=0.88)

  cites [14] Surmeier DJ, Obeso JA, Halliday GM. Selective neuronal vulnerability in Parkinson disease. Nat Rev Neurosci. 2017;18:101–13. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that oligomer types B and C entered cells and seeded intracellular α-synuclein aggregation. It suggests that seeding could contribute to the progression of pathology in Parkinson’s brains, but the study does not demonstrate cell-to-cell spread or aggregate formation throughout the brain. (LLM, conf=0.86)

  cites [15] Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B, Kostka M. Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27:9220–32. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [16] Danzer KM, Krebs SK, Wolff M, Birk G, Hengerer B. Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. J Neurochem. 2009;111:192–203. source
• Partly supported

  The paper’s opening section reports that introduced α-Syn fibrils seeded conversion of endogenous α-Syn into intracellular inclusions in cultured cells. But it says oligomeric α-Syn had little effect, and the Discussion says α-Syn fibrils were not efficiently taken up without a transduction reagent. It does not show cell-to-cell spread or aggregation throughout the brain. (LLM, conf=0.88)

  cites [17] Luk KC, Song C, O’Brien P, Stieber A, Branch JR, Brunden KR, Trojanowski JQ, Lee VM. Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6. sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports cell-to-cell α-syn transfer and seeding in the study’s models, and describes templated spread through progressively greater parts of the PD nervous system as a hypothesis. It does not establish that oligomers are particularly prone to uptake: the Discussion says monomeric, oligomeric, and fibrillar forms can all be internalized. Nor does it demonstrate aggregate formation throughout the brain. (LLM, conf=0.85)

  cites [18] Hansen C, Angot E, Bergstrom AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, et al. alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011;121:715–25. sourceExperimental — accuracy not yet measured
• Partly supported

  Section 5.1 reports that α-synuclein can seed aggregation in cultured cells and mice, while section 4.6 describes evidence for transport of inoculated α-synuclein fibrils along the vagus nerve. The paper does not establish that oligomeric species in particular are prone to cellular uptake and cell-to-cell spread, or that this mechanism produces aggregates throughout the brain in PD and DLB. (LLM, conf=0.85)

  cites [19] Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. Neuropathology and molecular diagnosis of Synucleinopathies. Mol Neurodegener. 2021;16:83. sourceExperimental — accuracy not yet measured

In the paper

“LRP1 mediates and regulates the endocytosis of > 30 ligands, including apolipoprotein E (APOE) and amyloid-β (Aβ) [21–27]”

What the sources say

• Partly supported

  The Introduction and the Structural and Functional Features section describe LRP1 as an endocytic receptor for diverse ligands. The Summary and Perspective identifies apoE as a major LRP1 ligand, and the Mechanisms of LRP1-Regulated Cellular Aβ Uptake section describes LRP1-mediated Aβ endocytosis. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.86)

  cites [21] Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-β clearance in Alzheimer’s disease. Frontiers in aging neuroscience. 2014;6:93. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) lists apolipoprotein E among ligands taken up through LRP1, and the Results section reports LRP1-mediated Aβ uptake in neuronal cells. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.87)

  cites [22] Kanekiyo T, Cirrito JR, Liu CC, Shinohara M, Li J, Schuler DR, Shinohara M, Holtzman DM, Bu G. Neuronal clearance of amyloid-β by endocytic receptor LRP1. J Neurosci. 2013;33:19276–83. sourceExperimental — accuracy not yet measured
• Partly supported

  The Biology of APOE section identifies LRP1 as an APOE receptor, and the Aβ clearance section describes LRP1-dependent cellular uptake of Aβ. Our copy does not support the specific claim that LRP1 mediates endocytosis of more than 30 ligands (searched: “LRP1 30 ligands” and “LRP1 more than 30 ligands endocytosis”). Page numbers were not available in the indexed passages. (LLM, conf=0.86)

  cites [23] Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15:501–18. sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘ApoE receptors’ section identifies LRP1 as an apoE-binding receptor, and ‘LRP1 in Aβ clearance’ reports that LRP1 affects neuronal Aβ uptake and trafficking. Our copy does not state that LRP1 mediates endocytosis of more than 30 ligands, so it does not support the claimed number. (LLM, conf=0.85)

  cites [24] Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, receptors, and modulation of Alzheimer’s disease. Biol Psychiatry. 2018;83:347–57. sourceExperimental — accuracy not yet measured
• Supported

  In “ApoE receptors, members of the LDLR family” (page not provided), the paper says LRP1 binds more than 30 ligands, including apoE, and transports ligands by receptor-mediated endocytosis. In “ApoE and apoE receptors in Aβ clearance and aggregation” (page not provided), it describes LRP1-mediated Aβ clearance and says these receptors can bind Aβ directly or through chaperones. (LLM, conf=0.91)

  cites [25] Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10:333–44. source
• Partly supported

  The Introduction describes LRP1 as regulating endocytosis of diverse ligands, and the Summary and Perspective identifies apoE as a major LRP1 ligand. The section on mechanisms of cellular Aβ uptake says LRP1 regulates Aβ endocytosis. Our copy does not give the claimed count of more than 30 ligands. (LLM, conf=0.86)

  cites [26] Kanekiyo T, Bu G. The low-density lipoprotein receptor-related protein 1 and amyloid-beta clearance in Alzheimer’s disease. Front Aging Neurosci. 2014;6:93. sourceExperimental — accuracy not yet measured
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [27] Robert J, Button EB, Martin EM, McAlary L, Gidden Z, Gilmour M, Boyce G, Caffrey TM, Agbay A, Clark A, et al. Cerebrovascular amyloid Angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E. Mol Neurodegener. 2020;15:23. source

In the paper

“We found that, similar to tau, LRP1-deficiency significantly reduced the cellular uptake of α-Syn (more than 75% reduction) in the iPSNs and consistent findings were observed from two different clones of LRP1-KO iPSNs (Fig. 2a, b, and c).”

In the paper

“We found that RAP strongly suppressed the neuronal uptake of α-Syn in a dose-dependent manner, whereas transferrin internalization was not affected (Fig. 2f).”

In the paper

“we found that the addition of N-α-Syn significantly inhibited the uptake of full-length α-Syn, whereas ΔN-α-Syn had no effect (Fig. 3d).”

In the paper

“We found that LRP1-KO effectively inhibited the uptake of N-α-Syn, to a similar extent as the full-length α-Syn but had no effect on ΔN-α-Syn uptake (Fig. 3c).”

In the paper

“After 14 days of culture, both WT and LRP1-KO cells exhibited a typical neuronal morphology and expressed the neuronal marker (Tuj1), suggesting the successful differentiation of NPCs into neurons (iPSNs) (Fig. 1c).”

In the paper

“Together, these data indicate that our strategy of deleting LRP1 in human iPSNs was successful and tau uptake was inhibited by LRP1 deletion in these cells.”

In the paper

“A recent study also identified LRP1 as a key regulator for the uptake and spread of microtubule-associated protein tau [29].”

What the sources say

• Not checked yetcites [29] Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, et al. LRP1 is a master regulator of tau uptake and spread. Nature. 2020;580:381–5. source

In the paper

“The low-density lipoprotein receptor (LDLR)-related protein 1 (LRP1) is a transmembrane receptor that belongs to the LDLR family [20].”

What the sources say

• ?Not checked — no full text of the sourcecites [20] Herz J, Bock HH. Lipoprotein receptors in the nervous system. Annu Rev Biochem. 2002;71:405–34. source

In the paper

“α-Syn has a high lysine content (15 lysines out of 140 aa, ~ 10%) with most (eleven) lysines located in the N-terminus, one lysine in NAC, and three in C-terminus (Fig. 3a).”

In the paper

“we confirmed that all the NPCs from the three lines were positive for neural precursor marker (Nestin) by immunostaining (Fig. 1b).”

In the paper

“Notably, LAG3 specifically binds to α-Syn PFFs but not monomers.”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [41] Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353:aah3374. source

In the paper

“Within the hippocampus, both GFP and h-α-Syn signal showed no significant differences between Lrp1-nKO and WT mice, indicating equivalent transduction of AAVs between the two groups (Fig. 4e, f and g).”

In the paper

“Karyotyping in each iPSC clones revealed the preservation of normal number and appearance of chromosomes (Fig. S2a).”

In the paper

“A recent study showed that the lymphocyte-activation gene 3 (LAG3) is a receptor for α-Syn PFFs which mediates the endocytosis and transmission of α-Syn PFFs between neurons [41].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [41] Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, et al. Pathological alpha-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353:aah3374. source

In the paper

“The finding may suggest that when forming the fibrils, the N-terminus of α-Syn is less exposed therefore the interaction between α-Syn and LRP1 might be limited.”

In the paper

“Monomeric α-Syn is composed of three domains: a lipid binding N-terminus domain (aa 1–60), a hydrophobic non-amyloid component (NAC) domain (aa 61–95), and a negatively charged C-terminus domain (aa 96–140) [2].”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites [2] Meade RM, Fairlie DP, Mason JM. Alpha-synuclein structure and Parkinson’s disease - lessons and emerging principles. Mol Neurodegener. 2019;14:29. source

In the paper

“Our findings support the hypothesis that LRP1 is a key regulator for both α-Syn and tau uptake and spread”