Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity induced brain pathology, female and male mice deficient in complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared to WD-fed WT mice, and to <jats:italic>C1qa</jats:italic> knockout (KO) and WT mice fed a control diet (CD). <jats:italic>C1qa</jats:italic> KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.</jats:p><jats:sec><jats:title>SIGNIFICANCE STATEMENT</jats:title><jats:p>Economic growth, an increasingly sedentary lifestyle and a nutritional transition to processed foods and high calorie diets have led to a significant increase in obesity prevalence. Several chronic diseases have been associated with obesity, including dementia. Obesity-induced, peripheral inflammation has been proposed as a possible trigger of pathological changes in the brain that lead to cognitive dysfunction and predisposition to dementia. Here we show that genetic deletion of the complement component C1QA prevents cerebrovascular damage, neuroinflammation and white matter degradation in a mouse model of western diet-induced obesity, demonstrating that inflammatory responses play a significant role in obesity-induced brain pathology. The complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity.</jats:p></jats:sec>

Differentially Expressed Genes and Enriched Signaling Pathways in the Adipose Tissue of Obese People

“…C1QB and C1QC belong to a family of complement proteins that are positively correlated with immune cell chemotaxis and can regulate the expression of the immune cells. Recent findings have revealed that C1Q-related gene knockouts can prevent obesity-related complications of Alzheimer’s disease ( Graham et al, 2020 ). FCGR2B and FCER1G are immunoglobulin fragments that regulate the immune response, and increase the likelihood of obese patients developing allergic diseases ( Mathur et al, 2013 ).…”

Microglial phagocytosis of neurons in neurodegeneration, and its regulation

“…Whether microglia could strip myelin off axons from live neurons remains unclear, but microglia do appear to survey myelin sheath in vivo (Zhang et al., 2019), and anti‐myelin antibodies or complement might promote such myelin stripping (DeJong & Smith, 1997; Vargas et al., 2010). Complement is activated in MS (Watkins et al., 2016), and C1q knock‐out mice were protected against white matter loss in a mouse obesity model, suggesting that C1q may mediate microglial phagocytosis of live myelin (Graham et al., 2020). Recently, it has been shown that C3, but not C1q, localize with synapses in several models of MS (Werneburg et al., 2020).…”