As described in chapter 2.4 of my book on neurodegeneration, activation of the brain's own immune cells, the microglia, is observed in Alzheimer's patients, especially in brain regions that are heavily affected by the disease. For example, in the entorhinal cortex of the temporal lobe, there are substantial protein deposits surrounded by activated microglia, but also by migrated T lymphocytes and pro-inflammatory cytokines.
Ultimately, such a 'sterile' inflammatory response leads to accelerated loss of synapses and neuronal death. The so-called complement system appears to play an important role in this process. Complement factors circulate in the blood as inactive precursors and are activated by pathogens or antibody-antigen complexes which then trigger a cascade of proteolytic reactions.
Microglial cells produce the first complement protein, the so-called C1 complex, which consists of C1q, C1r and C1s. It binds to neuronal plasma membranes and leads to phagocytosis, i.e. the affected synapses are cleared. Increased concentrations of complement factors are indeed detectable in the brains of Alzheimer's patients, and antibodies against complement protect synapses from their degradation.
Furthermore, in addition to microglia, astrocytes can also remove synaptic contacts. This is particularly evident during brain development. Unlike microglia, however, astrocytes appear to function independently of C1q under physiological conditions. In a study published last year in Nature Aging, Dejanovic and colleagues demonstrate that loss of C1q is neuroprotective in an animal model of Alzheimer's disease.
In these so-called TauP301S mice, astrocytes play a major role in eliminating synapses. In addition, microglial phagocytosis near plaques is also impaired in the absence of the Alzheimer's risk gene TREM2 which is particularly expressed in microglia. After its removal in so-called TREM2-knockout mice, astrocytes compensate for microglial dysfunction near amyloid plaques.
Taken together, the new results indicate that inhibition of complement may be a useful strategy to prevent neurodegeneration in AD. Since the absence of C1q protects against brain degeneration without preventing gliosis, i.e., reactive astrocyte proliferation, or even tau pathology, it is likely that the complement system is activated only after the onset of typical AD pathology. Thus, the complement factors act at the end of a long chain of events that ultimately lead to neuronal cell death.
Reference:
Dejanovic B, Wu T, Tsai M-C, ..., Hanson JE (2022) Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models. Nature Aging 2:837
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