Microglia are cells known as the “macrophages of the brain;” they degrade neuronal debris and dead or impaired neurons to maintain the health of the CNS. Previously thought to have this one-dimensional function, microglia are now shown to be implicated in the development of different neurodevelopmental and neurodegenerative diseases, such as Autism Spectrum Disorder (ASD) and Alzheimer’s Disease (AD), respectively. To understand their relationship in ASD and AD, it is essential to first understand their physiological role in the brain.
Microglia play four essential roles in the CNS; they survey and monitor through phagocytosis, synaptic pruning, programmed cell death, and neuronal plasticity. This means the growth and death of brain cells is heavily controlled by microglia. For example, mouse models show that during the critical period of development, microglial lysosomes contained pre- and postsynaptic structures. Aberrant synaptic pruning is one manifestation of ASD. Additionally, changes in microglial number or function during development can lead to aberrant neuroplasticity in adulthood, which affects long-term potentiation (how we learn) and other memory pathways. Studies show that patients with autism have aberrant microglial number and function in the dorsolateral prefrontal cortex that controls executive function.
Some individuals with autism have different expressions of microglia-related genes, like markers related to inflammation. This is significant since a phenotype of ASD is neuroinflammation and increased white brain matter tracks. Microglia impact inflammatory cytokines and molecules—such as interleukins or TNF—that affect synaptic plasticity, which can lead to the altered pruning of cortical synapses of ASD. An interesting finding included in this study is that there are sex differences in microglia function. A limitation that other studies intend to reveal is whether or not aberrant microglia is a cause or effect of the onset of ASD.
The same pathways that cause excess synaptic pruning can occur in AD patients and lead to common markers of dementia, like behavioural and cognitive dysfunction. Other factors such as comorbid depression in those with ASD and AD can also contribute to executive function declines, but not the visuospatial and verbal memory. It is important to understand the role of microglia in neurodevelopmental and neurodegenerative diseases since its pathways and relationship with other biomarkers—like soluble TREM2 or complement components in cerebrospinal fluid—can be used to detect at-risk individuals much earlier than if just observing symptomatic neuronal dysfunction itself. In the future, we should shift from using mouse models to investing in human induced pluripotent stem cell (iPSCs) microglia in order to determine the actual clinical therapeutic results of our findings.
Salter, M. W., & Stevens, B. (2017). Microglia emerge as central players in brain disease. Nature Medicine, 23(9), 1018–1027.