Excessive cholesterol in astrocytes linked to cognitive decline in Alzheimer's mice

 

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to progressive memory loss and a decline in mental functions. Several past studies have linked this disease to the accumulation of the protein amyloid-β into sticky plaques that disrupt the function of neurons.

More recently, neuroscientists have uncovered the existence of the glymphatic system, a brain-wide system that facilitates the clearance of metabolic waste, including amyloid-β in excess, from brain tissue via the flow of cerebrospinal fluid.

Astrocytes, the most abundant type of glial cells in the CNS, play a central role in this waste clearance process. These cells are known to regulate cerebrospinal fluid movement via a protein called AQP4 (aquaporin-4), supporting the clearance of waste from brain tissue.

Researchers at Sun Yat-Sen University and Sun Yat-Sen Memorial Hospital set out to better understand how anomalous calcium activity in astrocytes impacts the glymphatic system. Their findings, published in Nature Neuroscience, suggest that elevated calcium activity in astrocytes mediates an increase in cholesterol levels, which in turn impairs the function of the glymphatic system in a genetically engineered model of AD.

"Disruptions in the glymphatic system and its downstream meningeal lymphatic drainage pathway, crucial for brain waste clearance, are linked to the pathogenesis of AD, yet the underlying mechanisms remain unclear," wrote Zhan Zhang, Shaojian Li and their colleagues in their paper.

"Abnormal calcium dynamics in astrocytes represents an early event in the mouse models of AD. We show functional association between amyloid-β-induced elevation of Ca²⁺ dynamics in medial prefrontal cortex astrocytes and glymphatic dysfunction in cognitively impaired 5xFAD mice, which can be alleviated by the attenuation of G_q GPCR-evoked Ca²⁺ activity."

Studying a mouse model of Alzheimer's disease

As part of their study, Zhang, Li and their colleagues examined a genetically engineered mouse model of AD, known as 5xFAD mice. These mice carry five genetic mutations, three affecting the human APP (amyloid precursor protein) gene and two the human PSEN1 (presenilin-1) gene.

These genetic mutations are known to be associated with early-onset AD in humans. In mice, they produce some behaviors and brain changes that resemble those observed in human patients diagnosed with AD, including a formation of amyloid-β plaques, neuroinflammation, a loss of neurons in specific brain regions and memory impairments.

In their experiments, the researchers also measured calcium activity in astrocytes located within the mice's medial prefrontal cortex, a brain region known to support memory consolidation, decision-making, and the regulation of emotional responses. They also looked at how the accumulation of amyloid-β impacted the behavior of astrocytes and observed the functioning of the glymphatic system.

Zhang, Li and their colleagues also manipulated calcium signaling in the mice's brains and reduced the production of cholesterol in astrocytes using genetic techniques. They then observed how these interventions affected the function of the glymphatic system and the mice's mental functions.

"Mechanistically, Ca²⁺ hyperactivity increases cholesterol synthesis in astrocytes, leading to increased aquaporin-4 (AQP4) endocytosis and relocalization to lysosomes, thereby disrupting AQP4 polarity and glymphatic function," wrote the authors.

"Suppressing cholesterol synthesis by either specifically knocking down squalene epoxidase in astrocytes or atorvastatin administration improves glymphatic perfusion, meningeal lymphatic drainage and cognition performance in 5xFAD mice."

A possible path to slow down neurodegeneration

Overall, the team's observations suggest that an accumulation of amyloid-β increases calcium activity in astrocytes, which in turn disrupts the brain's waste clearance system. It also offers hints about how these processes might contribute to the cognitive decline and memory loss observed in patients with AD.

The researchers specifically found that increased calcium levels prompt a greater production of cholesterol in astrocytes, which in turn led to the misplacement of the protein AQP4. This protein helps to push waste out of the central nervous system by facilitating the flow of cerebrospinal fluid. Thus, its misplacement disrupts the glymphatic system.

Interestingly, Zhang, Li and his colleagues also found that reducing calcium activity or cholesterol improved the function of the glymphatic system. This also resulted in improvements in the mice's cognitive function and memory.

"Our data reveal potential therapeutic benefits of lowering astrocyte calcium activity and cholesterol synthesis for enhancing glymphatic–lymphatic coupling integrity in the early stages of AD pathogenesis," wrote Zhang, Li and their colleagues.

If they are validated in humans, the results of this study could have key implications for the early treatment of AD. Specifically, they could help to identify or design pharmaceutical drugs that might prevent or reverse cognitive decline in the early stages of the disease or slow down its progression.