C1q ablation exacerbates amyloid deposition: A study in a transgenic mouse model of ATTRV30M amyloid neuropathy

Abstract

ATTRV30M amyloid neuropathy is a lethal autosomal dominant sensorimotor and autonomic neuropathy, caused by deposition of amyloid fibrils composed of aberrant transthyretin (TTR). Ages of onset and penetrance exhibit great variability and genetic factors have been implicated. Complement activation co-localizes with amyloid deposits in amyloidotic neuropathy and is possibly involved in the kinetics of amyloidogenesis. A candidate gene approach has recently identified C1q polymorphisms to correlate with disease onset in a Cypriot cohort of patients with ATTRV30M amyloid neuropathy. In the current study we use a double transgenic mouse model of ATTRV30M amyloid neuropathy in which C1q is ablated to elucidate further a possible modifier role for C1q. Amyloid deposition is found to be increased by 60% in the absence of C1q. Significant up regulation is also recorded in apoptotic and cellular stress markers reflecting extracellular toxicity of pre-fibrillar and fibrillar TTR. Our data further indicate that in the absence of C1q there is marked reduction of macrophages in association with amyloid deposits and thus less effective phagocytosis of TTR.

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset

“…Certain polymorphic sites in C1q were previously found to correlate with the age of onset in Cypriot patients suggesting that complement C1q may indeed be a modifier [16]. Data from our group suggest that C1q ablation in TTRKO/Met30 +/+ transgenic mice enhances amyloid deposition, while upregulating apoptosis and oxidative stress [17,18]. Amyloid 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Epidemiology of this disease is evolving; patients are now diagnosed earlier and are offered more treatments.…”

“…agonists stimulate phagocytosis and reduce amyloid deposits [18,32]. It is therefore likely the C1q polymorphisms have a causative association with age of onset.…”

Amyloid Proteins and Peripheral Neuropathy

“…For example, macrophages in the sural nerve of AL patients are activated by amyloid and phagocytose and degrade amyloid protein aggregates and fibrils [ 73 ]. Similarly, macrophages are engaged in removal of TTR deposits in FAP patients [ 240 ] and FAP mouse models [ 265 , 266 , 267 ]. Macrophages also phagocytose β2M amyloid fibrils.…”

“…Indeed, reduced numbers of tissue macrophages as compared to non-diseased control tissue were observed in amyloid-containing hearts of FAP patients [ 270 ]. Moreover, in a mouse model expressing the V30M TTR mutant, impairing macrophage recruitment increased amyloid load and expression of apoptotic cell markers [ 267 ]. These data indicate that macrophage insufficiency may lead to amyloid accumulation and disease progression in FAP patients.…”

C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients

“…13 Recently, a double transgenic mouse model of Val30Met amyloid neuropathy in which C1q is ablated showed an increase in amyloid deposits by over 60%, compared to control mice. 14 The role of inflammation in the pathogenesis of the disease, both in the process of TTR misfolding and amyloid deposition and as a contribution to the process of nerve degeneration has been intensively studied in the last decade. More recently, the positive results of the double blind, randomized clinical trial with Diflunisal, 15 a nonsteroidal anti-inflammatory drug, raised the hypothesis that the anti-inflammatory effect could be superimposed on the TTR stabilizer effect, increasing the therapeutic potential of the drug.…”