Pharmacological Stimulation of Phagocytosis Enhances Amyloid Plaque Clearance; Evidence from a Transgenic Mouse Model of ATTR Neuropathy

Fella, Eleni; Sokratous, Kleitos; Papacharalambous, Revekka; Kyriacou, Kyriacos; Phillips, J. C.; Sanderson, Sam D.; Panayiotou, Elena; Kyriakides, Theodoros

doi:10.3389/fnmol.2017.00138

Cited by 7 publications

(7 citation statements)

References 59 publications

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“…The genetic analysis has found that C1q SNPs rs665691, rs158761, rs172378, rs672693, rs9434 and rs294180 correlate with an earlier age of disease onset. C1q activates the classical complement pathway ultimately producing the potent C5a anaphylatoxin, which in turn activates phagocytic cells and induces clearance of TTR amyloid deposits [32].…”

Section: Discussionmentioning

confidence: 99%

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

Andreou

Panayiotou

Michailidou

et al. 2018

Amyloid

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Background: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. Methods:The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out.Results: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years.Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16% respectively. C1q polymorphisms correlated with age of disease onset.Conclusion: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease.

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Section: Discussionmentioning

confidence: 99%

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

Section: Discussionmentioning

confidence: 99%

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

Andreou

Panayiotou

Michailidou

et al. 2018

Amyloid

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“…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.…”

Section: Mechanisms Linking Amyloid and Peripheral Neuropathymentioning

confidence: 99%

Amyloid Proteins and Peripheral Neuropathy

Asiri

Engelsman

Eijkelkamp

et al. 2020

Cells

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Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature—deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. Here, we will discuss how amyloid proteins contribute to peripheral neuropathy by reviewing the current understanding of pathogenic mechanisms in known inherited and acquired (usually rare) amyloid neuropathies. In addition, we will discuss the potential role of amyloid proteins in peripheral neuropathy in some common diseases, which are not (yet) considered as amyloid neuropathies. We conclude that there are many similarities in the molecular and cell biological defects caused by aggregation of the various amyloid proteins in these different diseases and propose a common pathogenic pathway for “peripheral amyloid neuropathies”.

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“…Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Timely activation of the innate immune mechanisms, as has been previously been shown in animal model of ATTRMet30 neuropathy, and presently with 5XFAD mouse model of AD offers an alternative therapeutic avenue[33].…”

Section: Discussionmentioning

confidence: 99%

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer’s disease

et al. 2019

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According to the amyloid hypothesis of Alzheimer’s disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.

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Pharmacological Stimulation of Phagocytosis Enhances Amyloid Plaque Clearance; Evidence from a Transgenic Mouse Model of ATTR Neuropathy

Cited by 7 publications

References 59 publications

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

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

Amyloid Proteins and Peripheral Neuropathy

C5aR agonist enhances phagocytosis of fibrillar and non-fibrillar Aβ amyloid and preserves memory in a mouse model of familial Alzheimer’s disease

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