Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders

Schmidt, A Floriaan; Finan, Chris; Chopade, Sandesh; Ellmerich, Stephan; Rossor, Martin N; Hingorani, Aroon D; Pepys, Mark B

doi:10.1101/2023.08.15.23293564

Cited by 2 publications

(1 citation statement)

References 64 publications

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“…GWAS data were accessed for the following traits: Alzheimer's disease (https://www.niagads.org/, from Kunkle et al), Lewy body dementia (https://www.ebi.ac.uk/gwas/publications/33589841), osteoarthritis (https://www.ebi.ac.uk/gwas/publications/30664745), systemic lupus erythematosus (https://www.ebi.ac.uk/gwas/publications/26502338), idiopathic pulmonary fibrosis (https://pubmed.ncbi.nlm.nih.gov/33197388/), systolic/diastolic blood pressure (https://www.ebi.ac.uk/gwas/publications/30224653), coronary heart disease (https://www.ebi.ac.uk/gwas/publications/36474045), type 2 diabetes (http://diagram-consortium.org/downloads.html, from Mahajan et al), liver enzymes (https://www.ebi.ac.uk/gwas/publications/33972514 and https://www.ebi.ac.uk/gwas/publications/ 33547301), brain volume (https://ctg.cncr.nl/software/summary_statistics, from Jansen et al), cerebral white matter hyperintensities (https:// www.ebi.ac.uk/gwas/publications/26674333), circulating total tau values (https://www.ebi.ac.uk/gwas/publications/35396452). All data needed to evaluate the conclusions in the paper are present in the paper and the electronic supplementary material [70].…”

Section: Opening Upmentioning

confidence: 99%

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Schmidt,

Finan,

Chopade

et al. 2024

Open Biol.

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The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 −3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 −5 ) and plasma tau concentration (0.06 log 2 (ng l −1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 −6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

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Section: Opening Upmentioning

confidence: 99%

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Schmidt,

Finan,

Chopade

et al. 2024

Open Biol.

View full text Add to dashboard Cite

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Serum Amyloid P Secreted by Bone Marrow Adipocytes Drives Skeletal Amyloidosis

Kumar,

Song,

Wang

et al. 2024

Preprint

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The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and is sufficient to promote the formation of insoluble amyloid deposits from soluble Aβ peptides in in vitro and ex vivo 3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aβ peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.

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Genetic evidence for serum amyloid P component as a drug target for treatment of neurodegenerative disorders

Cited by 2 publications

References 64 publications

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Serum Amyloid P Secreted by Bone Marrow Adipocytes Drives Skeletal Amyloidosis

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