Those who follow the developments in the treatment of Alzheimer’s disease are very well aware that the majority of treatments currently under development target, directly or indirectly, amyloid-beta protein and its derivatives. So far, unfortunately, this strategy brought nothing in terms of effective treatments. However, there are many different molecular participants involved in the development of the disease. It looks very likely that with a heavy focus on amyloid-beta, other potential avenues for therapeutic interventions have been overlooked.
Basics of amyloid theory
Alzheimer’s disease is a chronic neurodegenerative disease characterized by progressive dementia, the most common form of dementia worldwide, and may affect more than 5 million people in the US alone. Neuropathological hallmarks of Alzheimer’s disease include a build-up of toxic protein aggregates in the brain, including amyloid-beta plaques and tau tangles. In addition, Alzheimer’s disease is characterized by a loss neurons, as well as the synapses that are the points of contact for communication between neurons. Loss of synapses has been linked to cognitive decline in Alzheimer’s disease and other neurodegenerative diseases.
Researchers have tested different genes that may be contributing to disease risk. The first few genes discovered encode proteins that are involved in the production of amyloid and tau protein aggregates. Taken together, these findings have led to a prominent theory, where aggregation of toxic amyloid and/or tau proteins in the brain triggers Alzheimer’s disease—the so-called ‘amyloid cascade theory’ of Alzheimer’s disease. The theory is that accumulation of these toxic proteins triggers a cerebral cascade that is harmful to neurons and synapses, leading to progressive cognitive decline.
The amyloid cascade theory has been a major focus of research into the pathophysiology of Alzheimer’s disease and has guided the development of potential new treatments. While pharmacotherapies that target these proteins have proven to be effective at reducing amyloid burden, they have failed to improve cognitive functioning in clinical trials. Therefore, there are no effective treatments for Alzheimer’s disease to-date. Recent research has provided new avenues into additional potential causes of cognitive decline in Alzheimer’s disease.
Microglia: the brain’s scavengers
Recent large-scale genetic studies have found that genes that are associated with risk for Alzheimer’s disease are highly expressed in microglia. These results imply a potential role for microglia in Alzheimer’s disease pathophysiology. As the name implies, microglia are tiny glial cells, the support cells in the brain. Glial cells outnumber neurons by a ratio of nearly 4 to 1. Microglial cells act as the resident immune cells in the brain and play a unique role in neuroprotection and maintenance of homeostasis.
Microglia have been called the brain’s ‘scavenger cells’ because once activated, these cells can engulf cellular debris via a process known as ‘phagocytosis’. Therefore, microglia may protect nerve cells from damage by efficiently clearing potentially toxic protein aggregates, such as excess amyloid-beta. This clearing function has made microglia a promising target for Alzheimer’s disease treatments that are aimed at reducing amyloid protein load in the brain. During development, microglia also play a key role in removing excess synapses, a naturally-occurring process referred to as ‘synaptic pruning’.
A potential role for microglia in neurodegeneration
Although microglia play a key role in neuroprotection and homeostasis in the brain, their potential role in Alzheimer’s disease is unclear. Microglia have been thought to contribute to inflammation in response to disease neuropathology and may indirectly harm neurons and synapses by causing an increase in proinflammatory cytokines (e.g., interleukin-6 and tumor necrosis factor). However, a new study suggests that microglia may have a more direct role in neurodegeneration.
The recent research demonstrates that when microglia become activated, they can remove toxic protein aggregates associated with Alzheimer’s disease, but importantly, also remove synapses. Therefore, the process of synapse removal during development appears to be aberrantly reactivated, which may help to explain the link between amyloid burden and synapse loss in Alzheimer’s disease. This finding is important because it sheds new light on the reasons why drugs that have been effective at reducing protein load have not been effective at slowing cognitive decline. Dysfunctional microglia may therefore contribute directly to neurodegeneration in Alzheimer’s disease by removing synapses and enhancing cognitive decline.
The authors of this study caused microglia to become more active by turning off the gene that encodes the protein TDP-43 in microglial cells. TDP-43 is a DNA-RNA binding protein that regulates microglial phagocytosis, and when removed, the microglia become dysfunctional and remove amyloid protein as well as synapses. Interestingly, TDP-43 has been previously investigated for its potential central role in other neurodegenerative disease, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-U). In ALS, TDP-43 may contribute to neurodegeneration by increasing mitochondrial dysfunction.
A potential role for TDP-43 in Alzheimer’s disease, as well as Huntington’s and Parkinson’s disease, has only been the topic of investigation more recently. It was hypothesized that TDP-43 may contribute to mitochondrial dysfunction in Alzheimer’s disease or the production of amyloid plaques. Recent results unveil a new role for TDP-43 in Alzheimer’s disease pathophysiology, via microglial-induced pathological synaptic pruning. This may be critically important for early cognitive decline in Alzheimer’s, in that up-regulation of microglial phagocytosis in response to detection of excess protein aggregates may lead to removal of synapses, which in turn, causes cognitive decline. These findings are consistent with post-mortem studies of patients with Alzheimer’s disease, where TDP-43 levels are associated with the trajectory of cognitive decline (particularly episodic memory decline) and dementia.
These new findings are important because they provide evidence for a potential role of microglia in the pathogenesis of Alzheimer’s disease. They also raise important questions about the mechanisms involved in microglia-induced pathological synaptic pruning. Understanding these mechanisms could lead to the development of new treatments for Alzheimer’s disease that aim to retain the protein clearing action of microglia while preventing the pathological removal of synapses.
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