New research suggests that the innate immune system affects cognition by regulating synapse formation and maintenance. What role might this process play in Alzheimer’s, where immune cells become activated? At the Alzheimer's Association International Conference (AAIC), held July 13-18 in Boston, Massachusetts. Qiaoqiao Shi, working with Cynthia Lemere at Brigham and Women’s Hospital, Boston, reported that AD mice lacking a key component of the complement system have worse amyloid β (Aβ) pathology, but better memory, than their intact littermates. It is not yet clear why, but intriguingly, the mice with deficient complement systems retain more neurons and synapses as they age than their immune-competent brethren. In humans, brain amyloid load correlates poorly with cognition, whereas synaptic density shows a tight relationship with mental skills (see ARF related news story; DeKosky and Scheff, 1990).
The complement cascade comprises more than 20 small proteins that trigger microglia to gobble up harmful debris, such as Aβ deposits. In prior studies, researchers have found that AD mice lacking the central complement component C3 develop more Aβ pathology and neurodegeneration than do controls (see ARF related news story; ARF related news story). However, the complement also plays a role in maintaining synapses, with the C3b subunit cueing microglia to prune unneeded ones (see ARF related news story). This suggests that the complement system could contribute to the aberrant synapse elimination seen in AD, or even in normal aging. Intriguingly, complement components are more abundant in AD and Down’s Syndrome brains than in healthy controls, Lemere said. In addition, previous studies showed that the complement represses adult neurogenesis (see ARF related news story), which may contribute to new circuitry and synaptic plasticity.
To first investigate the role of the complement in aging, Shi, in collaboration with Beth Stevens at Boston Children’s Hospital, compared 16-month old C3 knockout and C3 receptor (CR3) knockout mice to age-matched controls. Both types of knockout had more neurons in the CA3 region of the hippocampus, and more synapses in several brain regions including CA3, dentate gyrus, and visual cortex, Shi reported at AAIC. (Other brain regions, such as the CA1, showed no difference between the knockouts and wild-type.) Hippocampal slices from the knockouts displayed stronger long-term potentiation, and both knockout strains performed better in the water T maze and in contextual fear conditioning trials than did aged controls.
Shi then crossed the knockouts with APP/PS1dE9 AD mice. As expected, the C3-deficient APP/PS1 offspring had more Aβ deposition in cortex and hippocampus at 16 months of age than did their APP/PS1 littermates. Shi traced this to poor phagocytosis of Aβ and fewer reactive astrocytes (see Fu et al., 2012). Despite the increased amyloid load, the C3-deficient APP/PS1 mice outperformed their APP/PS1 littermates with intact complement in the water T maze, learning as quickly as wild-type. Like the wild-type C3 knockouts, the complement-deficient APP/PS1 crosses also had more neurons in CA3 than did their APP/PS1 littermates.
The researchers do not yet know why the crossed mice learn better despite bearing more brain amyloid. It is possible that C3 mediates the toxic effects of Aβ, or that the brain can tolerate amyloid as long as it does not lose synapses, Lemere said. In people, education and cognitive activity early in life seem to build up a “cognitive reserve” that helps protect against Alzheimer’s disease for some time (see ARF related news story; ARF related news story). It also remains unclear why the effects of C3 deficiency vary by brain region and with age. More research is needed to tease out the mechanisms behind the sharper cognition, Lemere told Alzforum.
Lemere said the next step is to see if knocking down C3 after the brain has fully developed, or specifically in the hippocampus of aged AD mice, will be as beneficial as knocking it out from birth. If so, C3 inhibition might become a potential AD therapeutic approach. Small molecule inhibitors of human C3 exist. One was evaluated in a clinical trial for macular degeneration, since the complement system damages photoreceptors in that disease (see Qu et al., 2013; Whitcup et al., 2013).—Madolyn Bowman Rogers.
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- Dekosky ST, Scheff SW. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol. 1990 May;27(5):457-64. PubMed.
- Fu H, Liu B, Frost JL, Hong S, Jin M, Ostaszewski B, Shankar GM, Costantino IM, Carroll MC, Mayadas TN, Lemere CA. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia. Glia. 2012 May;60(6):993-1003. PubMed.
- Qu H, Ricklin D, Bai H, Chen H, Reis ES, Maciejewski M, Tzekou A, DeAngelis RA, Resuello RR, Lupu F, Barlow PN, Lambris JD. New analogs of the clinical complement inhibitor compstatin with subnanomolar affinity and enhanced pharmacokinetic properties. Immunobiology. 2013 Apr;218(4):496-505. PubMed.
- Whitcup SM, Sodhi A, Atkinson JP, Holers VM, Sinha D, Rohrer B, Dick AD. The role of the immune response in age-related macular degeneration. Int J Inflam. 2013;2013:348092. PubMed.
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