C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

Benoit, Marie; Hernandez, Michael; Dinh, Minhan L.; Benavente, Francisca; Vasquez, Osvaldo; Tenner, Andrea J.

doi:10.1074/jbc.m112.400168

Cited by 129 publications

(137 citation statements)

References 64 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…Indeed, whereas aging-related cognitive decline is known to coincide with synapse loss in the dentate gyrus of otherwise healthy humans and rats (Yankner et al, 2008;Morrison and Baxter, 2012), this aging-dependent synapse loss does not occur in mice (Calhoun et al, 1998). In concordance with our findings, C1q was recently shown to also have noncomplement cascadedependent modes of action (Benoit and Tenner, 2011;Naito et al, 2012;Nayak et al, 2012;Benoit et al, 2013), and novel roles in synaptic plasticity that are presumably cascade independent have recently been reported for several C1q-like molecules (Matsuda et al, 2010;Uemura et al, 2010;Bolliger et al, 2011). Interestingly, Naito et al (2012) discovered that C1q promotes agingassociated decline in tissue regeneration in the periphery and that this effect was independent of complement cascade execution but through canonical Wnt signaling.…”

Section: Discussionsupporting

confidence: 93%

“…C1q-deficient mice were generated by homologous recombination targeting exon 1 of the C1q(a) gene (Botto et al, 1998) and backcrossed for Ͼ10 generations to C57BL/6. C1q(a)-deficient mice (C57BL/6) have no C1q protein and disrupted classical complement activity (Botto et al, 1998). C3-deficient mice (C57BL/6), generated by homologous recombination targeting the coding sequence (nt 1850 -2214) of the C3 gene, were obtained from The Jackson Laboratory (B6 129S4-C3ϽtmCrrϾ/J; stock No.…”

Section: Methodsmentioning

confidence: 99%

“…Cognitive decline is one of the greatest health threats for the aging population (Bishop et al, 2010) and is caused by synaptic malfunction and/or synapse loss, rather than the loss of neurons per se (Yankner et al, 2008). The molecular mechanisms driving cognitive aging, in particular the ones that drive the synaptic changes are, however, unknown.…”

Section: Introductionmentioning

confidence: 99%

“…We recently found that C1q helps to mediate developmental CNS synapse elimination through classical complement activation which is crucial for finetuning the visual system circuitry (Stevens et al, 2007). Furthermore, C1q was shown to also act independently of classical complement, contributing to neuroprotection in the CNS (Benoit and Tenner, 2011;Benoit et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Madison²,

et al. 2013

View full text Add to dashboard Cite

The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement-and synapse elimination-independent role for C1q in CNS aging.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Madison²,

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The complement system regulates the activation of mononuclear phagocytes. The binding of C1q or cleavage products of C3 with the complement receptors on mononuclear phagocytes produce inflammatory cytokines [126,127], and promote phagocytosis of pathogens or apoptotic cells [128][129][130][131].…”

Section: Inflammation Versus Resolutionmentioning

confidence: 99%

Microglia and Monocyte-Derived Macrophages in Stroke

2016

View full text Add to dashboard Cite

Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.

show abstract

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

Dias

Santos

Coelho

et al. 2019

Ann Clin Transl Neurol

View full text Add to dashboard Cite

Objectives Transthyretin ( TTR ) familial amyloid polyneuropathy ( FAP ) ( OMIM 176300) shows a variable age‐at‐onset ( AO ), including within families. We hypothesized that variants in C1 QA and C1 QC genes, might also act as genetic modifiers of AO in TTR ‐ FAP Val30Met Portuguese patients. Methods We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations ( GEE s) to take into account the non‐independency of AO among relatives. Intensive in silico analyses were performed, using various software to assess mi RNA s target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions. Results Two variants for C1 QA gene, GA genotype of rs201693493 ( P < 0.001) and CT genotype of rs149050968 ( P < 0.001), were significantly associated with later AO . In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1 QC , we found three statistically significant results: GA genotype of rs2935537 ( P = 0.003), GA genotype of rs201241346 ( P < 0.001) and GA genotype of rs200952686 ( P < 0.001). The first two were associated with earlier AO , whereas the third was associated with later‐onset. Interpretation C1 QA was associated with later onset, whereas C1 QC may have a double role: variants may confer earlier or later AO . As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR ‐ FAP Val30Met.

show abstract

C1q-induced LRP1B and GPR6 Proteins Expressed Early in Alzheimer Disease Mouse Models, Are Essential for the C1q-mediated Protection against Amyloid-β Neurotoxicity

Cited by 129 publications

References 64 publications

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

A Dramatic Increase of C1q Protein in the CNS during Normal Aging

Microglia and Monocyte-Derived Macrophages in Stroke

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

Contact Info

Product

Resources

About