Removing C1q in Mice Reduces Cognitive Decline With Aging

The protein C1q is related to the processes of Wnt signaling, a name which might be more familiar to those who follow research into the molecular biochemistry and genetics of aging. Wnt shows up in all sorts of areas related to development and regeneration, and a range of research groups are investigating this area of biology. Levels of C1q increase with aging, and genetic engineering to remove C1q in mice was shown to be beneficial, producing an increase in regenerative capacity:

We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. ... Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption.

More recent research now shows that eliminating C1q also reduces the mental decline associated with aging in mice. This might operate through similar underlying mechanisms to those that improve muscle regeneration, such as by a boost to the ability to generate new neurons and maintain neural tissue and blood vessels in the brain in better functioning condition.

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

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 central nervous system.

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.


So, how do we make this work for those persons who have early stage Alzheimer's disease to the point where the C1q would be reduced and the cognitive decline reversed?

Posted by: John Neely at September 18th, 2013 1:15 PM

I think that this line of thinking is very interesting and definately worthy of more investigation. My father is in the first stage if Alzheimer's and to find a way to stop or repress this process would be awesome. The future increase of this brain disfunction in our aging population i believe will bring this type of research to the forfront to hopefully introduce a clinically usable product that prolongs cognitive function for aging people. Another thought would be to go backwards and discover the trigger that starts the increase C1q and make a blocker gene that could stop this before it progresses.

Posted by: Mark MacBain at December 23rd, 2013 11:08 AM
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