Despite decades of rigorous investigation, the mystery of why neurons deteriorate in neurodegenerative diseases like Alzheimer’s remains unresolved, raising profound questions about the mechanisms behind these devastating conditions. Originally, scientists thought that Alzheimer's disease stemmed primarily from the accumulation of two proteins—amyloid and tau—that, under normal circumstances, support neural growth, repair, and structural stability. The logic was straightforward: these proteins become toxic when they accumulate, so breaking them down should restore brain health. Yet, even with this targeted approach, clinical trials showed that patients experienced only minimal cognitive improvements, if any, suggesting that the story of Alzheimer's may be far more complex.

This disappointing outcome spurred scientists to search for additional culprits. In 2004, George Bartzokis, a neuroscientist at UCLA, proposed a groundbreaking theory: what if the myelin sheath—the insulating layer around axons essential for neuronal survival, efficient signaling, and memory formation—was a critical piece of the puzzle? To test this, researchers turned to aged rhesus monkeys, whose myelin showed signs of degradation similar to those observed in human Alzheimer’s patients. Could myelin breakdown, rather than just protein accumulation, drive neurodegeneration? 

As they uncovered these myelin changes, researchers wondered: what other hidden factors lie dormant in the brain, waiting to be discovered? Could other cellular structures or overlooked metabolic processes contribute to the disease? This layered mystery left scientists and clinicians grappling with even more questions, each discovery both illuminating and deepening the enigma of Alzheimer's.

When scientists examined brain scans through MRI studies in humans, they discovered signs of myelin damage as early as two decades before the onset of Alzheimer's disease. This finding suggested an intimate connection between early myelin degeneration and cognitive decline, pointing to myelin damage as a potential early indicator in the disease’s progression. But, despite these findings, researchers largely dismissed the possibility that myelin deterioration could drive Alzheimer's, instead presuming it to be a consequence of neuron loss. As a result, nearly 20 years passed without substantial follow-up studies to investigate this connection further.

Recently, however, researchers at the Third Military Medical University and the University of California, San Francisco, challenged this assumption by observing not only myelin degeneration in Alzheimer's mouse models but also an unexpected, high rate of myelin repair. Intriguingly, even though the repair couldn’t fully counteract the damage, enhancing myelination significantly improved cognition and neuronal health—regardless of amyloid buildup. This opens up several pressing questions: could myelin be playing a larger, independent role in Alzheimer's than previously thought? And if myelin damage might also drive amyloid accumulation, as recently proposed by scientists at the Max Planck Institute, does this mean the entire disease pathway needs reevaluation? As researchers grapple with these unknowns, they face a fundamental mystery: have we misunderstood the early signs and drivers of Alzheimer’s all along?

The Link Between Microglia and Myelination: A Mystery Deepens

While recent studies on microglia have offered answers, they have also opened new doors to puzzling, unresolved questions. Understanding the causes of myelin degradation could hold the key to preventing the onset of dementia and other neurodegenerative diseases. But what, exactly, triggers myelin breakdown? And how does myelin maintain its structure and functionality in a healthy brain? In search of these answers, researchers turned their focus toward an unlikely ally within the brain: microglia.

Microglia, a specialized subset of glial cells, act as the immune defenders of the central nervous system, constantly scanning the brain's environment for pathogens, injuries, or other threats. Recently, however, scientists discovered that microglia do far more than merely protect—they also support healthy brain function and play a continuous role in myelination, the process of forming the protective myelin sheath around neurons. Experiments with young mice even suggested that microglia help drive myelin production by promoting the growth of oligodendrocytes, the cells responsible for myelin synthesis. But this realization led to another question: could other types of immune cells also play a role in myelination? The existing techniques used to study microglia often inadvertently affected a neighboring immune cell group, border-associated macrophages, leaving their role in myelination uncertain.

In 2019, a breakthrough occurred. Researchers at the University of Edinburgh developed a unique mouse model using CRISPR-Cas9 gene editing, selectively deleting the FIRE sequence, a super enhancer required for microglia survival but not for border-associated macrophages. This allowed scientists, for the first time, to observe microglia’s unique contributions to myelination. Yet, even with this advanced model, fundamental questions linger. Why do microglia support myelin in some situations but trigger its degradation in others? And could border-associated macrophages have hidden, indirect effects on the myelination process, even when they appear uninvolved? As researchers delve deeper, the mystery only seems to grow, with every answer unveiling new layers of complexity and unknowns, leaving scientists and clinicians alike on the edge of discovery.

In our lab at the University of Edinburgh, we delved into the mysteries of myelin growth by studying FIRE mice, which naturally lack microglia. We believed that without microglia, these mice would show impaired myelination during early development. This hypothesis aligned with prior studies using models that broadly depleted macrophages. But the reality turned out to be far more enigmatic.

Upon examining the FIRE mice, we found no evidence of a myelin deficit. Confounded, we spent months investigating every angle—analyzing myelin-associated proteins, counting oligodendrocytes, and testing different developmental stages. Yet, everything appeared normal. Finally, using electron microscopy to examine brain tissue at an ultrastructural level, we uncovered a stunning twist: these mice, in fact, had an excess of myelin. The absence of microglia had led to an unexpected overproduction of myelin that persisted into adulthood.

This discovery posed even more questions. How could microglia, previously thought to merely support brain cells, actually control the amount of myelin? Were they perhaps playing a more active regulatory role than we had ever imagined? To test our theory, we tried depleting microglia in adult mice with a pharmacological agent. Astonishingly, these mice also developed excess myelin in just one month.

Curiosity led us to ask whether this phenomenon extended to humans. Collaborating with neuropathologist Werner Stenzel, we examined tissue from patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a rare disease involving CSFIR gene mutations that reduce microglial presence. In these patients, we found strikingly similar myelin overgrowth, suggesting that microglia may have a crucial, universal role in regulating myelin. The revelations left us wondering: what other hidden roles might microglia play, and how could these findings reshape our understanding of neurodegenerative diseases? The mysteries deepened.

The discovery that microglia not only control the formation of myelin during early development but continue to influence myelin growth well into adulthood unveils intriguing new questions. What, exactly, is the role of microglia in balancing myelin production, and could their absence or dysfunction accelerate the brain's aging process? When researchers reduced or removed microglia in animal models, an unexpected consequence emerged: myelin growth surged out of control, bearing a striking resemblance to the abnormal myelin patterns seen in older primates suffering from cognitive decline. Could this abnormality signal the onset of cognitive disorders, even in younger subjects?

Curious to explore the cognitive impacts further, scientists turned to the FIRE mice, testing their ability to learn and adapt within the Barnes Maze—a task designed to assess spatial memory and flexibility. In these trials, after the mice learned to find an escape hole in the maze, researchers moved the hole to a new location, observing how quickly the mice adapted to the change. Surprisingly, the FIRE mice struggled, showing marked deficits in cognitive flexibility. This deficit, which typically appears in aging animals, raises troubling questions: could this early decline foreshadow conditions like Alzheimer's, and how closely are microglia linked to preserving cognitive health over a lifespan? The answers remain elusive, deepening the mystery.

Microglia's role in myelin protection against degeneration is a puzzle with far-reaching implications. Knowing that aging disrupts myelin structure and that myelin degeneration is a hallmark of Alzheimer’s disease, we became curious about whether the structural changes observed in the absence of microglia might accelerate myelin vulnerability to degeneration. Our findings in samples from patients with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented glia (ALSP) suggested further questions. In a younger patient who had died from unrelated causes, myelin appeared unusually abundant and thick. But in an older patient, much of the myelin had broken down, with only remnants of overgrown structures. Why would myelin, in the absence of microglia, become both excessively grown and prone to breakdown?

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Intrigued, we looked closer at FIRE mice, a model lacking microglia, and by six months, we observed rapid myelin degeneration. What was responsible for this? When we pharmacologically depleted microglia and macrophages in older, otherwise healthy mice, similar myelin breakdown emerged. This deepened the mystery: if microglia play such a critical role in myelin health, what exactly do they do to protect it, and why does this role become more vital with age? Could we be overlooking another unknown factor driving this rapid degeneration? Our findings raise as many questions as they answer, leaving us to wonder how microglia interact with myelin at a molecular level—and whether restoring their function could help slow the progression of neurodegenerative diseases.

The concept of "microglia burnout" opens a new realm of questions and mysteries in the battle against neurodegenerative diseases. Much like human burnout, this phenomenon suggests that microglia—the immune cells of the brain—may experience a debilitating fatigue, unable to keep up with the ever-increasing demands placed upon them as we age. But how does this burnout unfold? What exactly triggers it? Could there be a tipping point when microglia, after years of managing cellular cleanup, myelin maintenance, and inflammatory responses, simply reach their limits?

In aging brains and in diseases like Alzheimer's, a special type of microglia appears, as shown in intricate single-cell transcriptomic studies. This disease-associated microglia population may signal a cellular cry for help, but is it merely a response to the stress of an aging brain, or is it part of the very mechanism driving neurodegeneration? Scientists are left to wonder: If we could somehow restore these cells to their younger, more resilient state, could we not only stave off dementia but actually protect the brain’s essential structures, like myelin?

Yet, this line of inquiry reveals another mystery: could rejuvenating microglia actually prevent or even reverse brain aging, or would it have unforeseen consequences? As researchers dig deeper, each answer seems to bring new layers of unknowns, leaving us to wonder how close we truly are to understanding the mind’s most silent guardians.