Excess Fat Disrupts Brain Immunity in Alzheimer's Disease

Recent research from Purdue University has revealed that the accumulation of fat in the brain plays a significant role in the progression of neurodegenerative diseases, particularly Alzheimer's disease. This finding challenges the long-held belief that fat in the brain is inconsequential to such conditions.

The study, published in the journal Immunity, highlights how excess fat in microglia, the brain's resident immune cells, compromises their ability to respond effectively to disease. This breakthrough opens new avenues for lipid biology-based neuroimmune therapies aimed at enhancing microglial function and neuronal health in patients with Alzheimer's.

Traditionally, Alzheimer's drug development has focused primarily on the disease's hallmark pathologies, such as amyloid beta plaques and tau protein tangles. However, the research led by Professor Gaurav Chopra emphasizes the critical role of fat-laden microglia surrounding affected brain areas.

In prior studies, Chopra and his team discovered that astrocytes, another type of supportive brain cell, release fatty acids that can be toxic to neurons in diseased conditions. Collaborating with researchers from the University of Pennsylvania, they also established a connection between mitochondrial dysfunction in neurons and fat deposits in glial cells, which are significant risk factors for neurodegeneration.

Chopra argues that addressing the plaques or tangles alone is insufficient for combating Alzheimer's. Instead, there is a need to restore the functionality of immune cells in the brain. He notes that reducing fat accumulation in the brain is crucial, as excess fat hampers the immune system's ability to maintain homeostasis. The research indicates that by targeting the pathways responsible for fat accumulation, it may be possible to rejuvenate microglial activity and, in turn, enhance the brain's defense mechanisms.

The collaborative efforts with Cleveland Clinic, led by Professor Dimitrios Davalos, further strengthen the research findings. Chopra's work aligns with Purdue's presidential One Health initiative, which promotes interdisciplinary research on human, animal, and plant health, particularly in advanced chemistry.

Historically, the presence of lipid droplets in Alzheimer's disease was considered a mere by-product of the condition. However, the new insights from Chopra's team suggest a more complex relationship between neurodegenerative diseases and lipid accumulation in microglia and astrocytes. This research introduces a novel 'lipid model of neurodegeneration,' with the term 'lipid plaques' being proposed for these harmful fat accumulations.

In their study, the researchers focused on microglia, which are responsible for clearing debris such as misfolded proteins via a process known as phagocytosis. They observed that microglia located near amyloid beta plaques contained significantly more lipid droplets than those situated further away. Notably, microglia nearest these plaques cleared approximately 40% less amyloid beta compared to microglia from healthy brains.

Investigating the impairment of microglia in Alzheimer's, the team found that those in close proximity to amyloid beta plaques produced excessive free fatty acids. While some production of these fatty acids is beneficial, microglia near amyloid plaques converted them into triacylglycerol, a stored fat form. This conversion led to an overload of fat, immobilizing microglia and impairing their function.

Moreover, the research identified abnormally high levels of the enzyme DGAT2, which plays a key role in converting free fatty acids into stored fat. Interestingly, the enzyme was found to accumulate not due to overproduction but because it was not breaking down as it should. This buildup contributes to the dysfunction of microglia, impairing their ability to clear amyloid beta.

Efforts to address this issue included testing molecules that inhibit DGAT2's function and promote its degradation. Results indicated that reducing DGAT2 levels improved microglial function, enabling them to better clear amyloid beta and enhancing neuronal health in animal models of Alzheimer's disease.

The implications of this research are significant, suggesting a new therapeutic target for Alzheimer's treatment through the modulation of lipid metabolism in brain immune cells. The findings indicate that by restoring the metabolic processes of microglia, it may be possible to rejuvenate the brain's innate defense mechanisms against Alzheimer's and potentially other neurodegenerative conditions.