August 20, 2024
By adminAbout 50 million people deal with Alzheimer's disease or age-related dementia. This number is expected to jump to over 152 million by 20501. Researchers have often ignored the role of brain cells like astrocytes, microglia, and oligodendrocytes in Alzheimer's. This review will show how these glial cells are key to understanding the disease.
For a long time, Alzheimer's was seen as a disease of neurons, with a focus on amyloid-beta plaques and tau tangles. But now, we know that most Alzheimer's cases are mixed with other conditions like cerebrovascular disease1. This new understanding highlights the importance of studying how neurons and other brain cells work together in Alzheimer's.
Key Takeaways
- Alzheimer's disease (AD) is a common form of dementia, affecting around 50 million people worldwide, with projections to exceed 152 million by 2050.
- Pure AD makes up less than half of all cases, with most patients showing signs of cerebrovascular disease and mixed dementia.
- The interaction between neurons and cells like astrocytes, microglia, and oligodendrocytes is vital for understanding Alzheimer's disease.
- Research is looking into how ROS, inflammation, and changes in the brain's blood vessels affect Alzheimer's.
- The amyloid cascade theory points to amyloid-beta as a major part of Alzheimer's, linked to certain gene mutations.
Understanding Alzheimer's Disease: A Global Health Priority
Alzheimer's disease (AD) is a major type of dementia that causes a slow loss of memory and thinking skills2. It affects about 50 million people worldwide and could reach over 152 million by 20502. The main signs of AD include amyloid-beta plaques and neurofibrillary tangles in the brain2.
But AD is not just one type of dementia. It's part of a bigger group, making up less than half of all dementia cases3. Many people have a mix of AD and other brain diseases, showing how complex it can be3.
Prevalence and Projections
AD is the main cause of dementia, affecting 60%–80% of dementia cases worldwide3. In 2019, there were about 57.4 million people with dementia, and deaths from AD went up by over 145% from 2000 to 20193. In the U.S., AD is the sixth leading cause of death, affecting around 5.5 million people4.
Genetics play a big role in AD, with some genes increasing the risk a lot3. Having a certain gene can make the risk 3–4 times higher, and two copies can increase it even more3. Being older also raises the risk, with more people over 65 and 85 being affected3.
Pathological Hallmarks: Amyloid Plaques and Neurofibrillary Tangles
The main signs of AD are Aβ plaques and neurofibrillary tangles in the brain2. These changes happen in areas important for memory and thinking, leading to the symptoms of AD2.
Some older people without AD can also have Aβ plaques, showing that these alone don't always cause the disease4. The full picture of AD includes many factors, like inflammation and problems with blood vessels, which are key to understanding the disease4.
"Alzheimer's disease is a global health priority, with its prevalence and associated burden expected to rise dramatically in the coming decades. Understanding the multifaceted nature of this complex disorder is crucial for developing effective prevention and treatment strategies."
The Amyloid Cascade Hypothesis: A Dominant Theory
The amyloid cascade hypothesis is a leading theory in Alzheimer's disease (AD) research for over 30 years5. It says that the processing of amyloid precursor protein (APP) is key to understanding AD5. This process involves the cutting of APP by beta-secretase (BACE) and then by gamma-secretase to form amyloid-beta (Aβ) peptides, especially the harmful Aβ42 and Aβ40 types5.
Amyloidogenic Processing of Amyloid Precursor Protein
This theory proposes that too much or not enough Aβ clearance leads to their clumping. This starts a chain of events that damages brain cells and worsens memory loss6. Mutations in APP and presenilin genes, part of the gamma-secretase complex, are linked to inherited Alzheimer's disease7.
Role of Presenilin Mutations in Familial Alzheimer's Disease
Familial Alzheimer's disease (FAD) is a rare, inherited type, making up less than 5% of cases7. Mutations in PSEN1 and PSEN2 genes cause FAD by affecting the gamma-secretase complex and boosting Aβ42 production7. On the other hand, most Alzheimer's cases, known as sporadic Alzheimer's, are caused by a mix of genetic and environmental factors6.
"The amyloid cascade hypothesis is a dominant theory that has driven Alzheimer's disease research for the past three decades."
Vascular Dysfunction: A Key Player in Alzheimer's Pathogenesis
New studies show that vascular problems are key in Alzheimer's disease (AD)8. Amyloid-beta (Aβ) plaques and neurofibrillary tangles, signs of AD, are found mainly in the neocortex and hippocampus8. Research also points out that early damage to brain myelin can make Aβ build up in the hippocampal white matter and cortex8.
Cerebrovascular Pathologies in Alzheimer's Disease
People with AD often see a drop in brain myelin, linked to more microglia8. This myelin loss is seen in AD autopsy samples8. Mice with myelin issues had less myelin in the brain's upper layers and more Aβ plaques in certain areas8.
Amyloid-Beta Production and Clearance Imbalance
AD brings vascular issues like strokes, hemorrhages, and brain damage8. These problems can change how Aβ is made and cleared, leading to more Aβ plaques in the brain8. Aged mice without the human APP gene but with myelin problems didn't have amyloid plaques, showing how vascular issues affect AD8.
Understanding vascular issues in AD highlights the need for a broad approach to tackle this disease9. Focusing on the vascular system and its effects on Aβ could lead to new treatments for Alzheimer's9.
| Statistic | Value |
|---|---|
| Alzheimer's disease affects over 47 million people globally | 9 |
| Estimated 131 million individuals may be affected by Alzheimer's disease by 2050 | 9 |
| Prevalence of Alzheimer's disease is approximately 10% for individuals over 65 years and 40% for those over 80 years | 9 |
| Less than 1% of Alzheimer's cases are dominantly inherited familial AD | 9 |
| Early onset Alzheimer's disease accounts for fewer than 5% of pathologically diagnosed cases | 9 |
Recent research has deepened our understanding of vascular dysfunction in Alzheimer's disease10. It shows that oligodendrocytes, key brain cells, produce a lot of amyloid-beta10. In fact, a significant part of brain Aβ comes from these cells in a specific AD model10. This highlights the big role of vascular and myelin factors in Alzheimer's disease.
Neuronal-Glial Crosstalk: Unraveling the Complexity
For a long time, we've focused on neurons. But now, we see how important glial cells like astrocytes and microglia are in Alzheimer's disease (AD)11. These cells help cause inflammation in the brain, a key sign of AD, by talking to neurons and other brain parts11.
Astrocytes and Microglia: Key Players in Neuroinflammation
Astrocytes and microglia are key immune cells in the brain. They help create inflammation in AD11. They release chemicals that harm neurons and work together to cause cell loss11. New studies show how these cells work together, showing their big role in AD.
Oligodendrocyte Progenitor Cells and White Matter Damage
AD also harms the brain's white matter11. This happens when cells called oligodendrocyte progenitor cells don't fully develop and when myelin, a protective layer, is lost11. Knowing how neurons, astrocytes, microglia, and these cells interact is key to understanding AD.
"The interaction between neurons and glial cells is a complex and dynamic process, with profound implications for the development and progression of neurodegenerative diseases like Alzheimer's." - Dr. Sarah Williams, Neuroscientist
Understanding how neuronal-glial crosstalk affects inflammation, brain health, and neurodegeneration is vital. It helps us learn more about AD and could lead to better treatments11.
Alzheimer's disease,glial cells,oligodendrocytes,amyloid beta,neurons,plaques
Alzheimer's disease is a major focus of research12. Recent studies highlight the key role of glial cells, especially oligodendrocytes, in the disease. These cells make up about 30% of the brain's amyloid load, showing they are crucial in Alzheimer's12.
The amyloid cascade hypothesis says amyloid-beta (Aβ) buildup in the brain causes Alzheimer's. Studies show removing the BACE1 gene in neurons cuts plaque formation by over 95%12. Oligodendrocytes without BACE1 also show a 30% drop in plaque formation12. This shows how neurons, glial cells, and the amyloid-beta pathway interact in Alzheimer's.
Alzheimer's affects not just neurons but also the balance between brain cell types13. Glial cells like microglia, astrocytes, and oligodendrocytes support neurons but can malfunction in the disease, causing inflammation and harming neurons13.
| Cell Type | Role in Alzheimer's Disease |
|---|---|
| Oligodendrocytes | Contribute up to 30% of the brain's beta-amyloid load, and their depletion of BACE1 leads to a 30% reduction in plaque formation12. |
| Microglia | Malfunctioning microglia can release chemicals causing chronic inflammation, further damaging the neurons they are supposed to protect13. |
| Astrocytes | Faulty astrocytes can also contribute to chronic inflammation in the brain, harming the neurons they are meant to support13. |
Our understanding of Alzheimer's is growing, and research on glial cells, especially oligodendrocytes, is leading to new treatments12. With $3.8 billion spent on Alzheimer's research yearly, focusing more on glial cells could lead to breakthroughs and new treatments12.
"Research involving glial cells, specifically oligodendrocytes, is rapidly reshaping our understanding of Alzheimer's disease and could lead to new therapeutic developments."
Microglia: Guardians or Culprits in Alzheimer's Disease?
Microglia are key immune cells in the brain, crucial for Alzheimer's disease (AD) development. They help shape how neurons work and connect14. These cells are also dynamic, helping form new connections by releasing brain-derived neurotrophic factor14. Yet, they can also cause problems as we age and in Alzheimer's disease14.
TREM2 and Microglial Activation
The receptor TREM2 helps activate microglia to clear amyloid-beta, a key Alzheimer's marker15. Without TREM2, microglia can't protect the brain well, leading to more amyloid and brain damage14. Microglia from Alzheimer's mice show signs of inflammation and dysfunction, pointing to their complex role in the disease14.
Microglia-Mediated Amyloid-Beta Compaction and Clearance
Microglia are vital for removing amyloid-beta from the brain. They can engulf and clear out this harmful protein with the help of the complement system14. C3 and receptor type 3 are key in this process14. But, the complement system also helps keep the brain's immune system in check, showing microglia's complex role in Alzheimer's14.
As we learn more about microglia and Alzheimer's, it's clear they can be both protectors and contributors to the disease15. Focusing on microglia, like TREM2 and amyloid-beta removal, could lead to new treatments for Alzheimer's15.
Astrocytes: Multifaceted Roles in Alzheimer's Pathogenesis
Astrocytes are the most common glial cells in the brain. They are key in the development of Alzheimer's disease (AD). Since 1856, research has shown how important astrocytes are in understanding Alzheimer's16. Studies in journals like Neuroglia, Glia, and Frontiers in Cell Neuroscience have greatly helped us learn about astrocytes' roles16.
Amyloid-Beta Degradation and Clearance
Astrocytes can break down amyloid-beta (Aβ), a major sign of AD. They do this in both lab tests and real-life situations. They have enzymes like insulin-degrading enzyme and matrix metalloproteinases to help with this17.
But, as people get older, astrocytes make less of these enzymes. This makes it harder for them to help the brain and clear out Aβ17.
Calcium Signaling and Neuronal Hyperactivity
Aβ affects astrocyte calcium levels, making them overactive and harming neurons. This imbalance in calcium is a big part of why Alzheimer's happens17. Research in FEBS Letters and Nature Neuroscience shows how astrocytes change and their role in the brain16.
"The role of astrocytes in Alzheimer's disease is multifaceted and encompasses not only Aβ degradation and clearance but also the regulation of calcium signaling and neuronal activity."
Astrocytes are very important in Alzheimer's disease. They help by breaking down Aβ and managing calcium levels and neuron activity. Knowing how astrocytes work with other brain cells is key to finding new treatments for Alzheimer's1617.
Oligodendrocytes and Myelin Sheath: The Forgotten Players
Many people focus on neurons in Alzheimer's disease, but oligodendrocytes, the cells that make the myelin sheath, are often ignored18. Studies show that damage to the myelin sheath in areas like the hippocampus and entorhinal cortex happens before the typical signs of Alzheimer's appear18.
Myelin Sheath Integrity and Neuronal Connectivity
When oligodendrocyte progenitor cells don't fully develop and the myelin sheath is damaged, it can lead to problems with how neurons connect and work together18. In mice that mimic Alzheimer's, these issues start early and get worse over time18. They also show changes in the brain areas important for memory, showing how crucial oligodendrocytes are18.
Oligodendrocyte Progenitor Cell Differentiation and Remyelination
As mice with Alzheimer's get older, new oligodendrocytes start to form in certain brain areas, but the total number stays the same18. This could be a sign that the brain is trying to fix the damage18. Helping these cells develop and repair the myelin sheath might be a new way to treat Alzheimer's by improving how neurons work together18.
We need more studies to understand how oligodendrocytes and the myelin sheath affect Alzheimer's disease19. By learning more about these cells, we might find new ways to stop or slow Alzheimer's down19.
| Oligodendrocyte Progenitor Cell Markers | Myelin Sheath Characteristics |
|---|---|
|
|
"Targeting OPC differentiation and remyelination could be a promising therapeutic approach for Alzheimer's disease."
Neuro-Vascular Unit Dysfunction in Alzheimer's Disease
Alzheimer's disease (AD) is a complex disorder that affects both neurons and blood vessels. The neurovascular unit (NVU) is key to keeping the blood-brain barrier strong and controlling blood flow to the brain20.
Blood-Brain Barrier Impairment and Leukocyte Infiltration
In AD, the NVU's pericytes don't work right, causing the blood-brain barrier to break down. This lets harmful immune cells into the brain21. These cells start an inflammatory response that hurts neurons and glial cells more.
Cerebral Blood Flow Dysregulation and Hypoperfusion
AD also harms the blood vessels, making it hard to control blood flow and reducing it20. This lack of blood hurts neurons and glial cells and leads to more amyloid-beta (Aβ) buildup21. Aβ on brain blood vessels makes things even worse.
The problems with blood vessels, inflammation, and Aβ create a cycle that worsens Alzheimer's disease20. Understanding how the NVU works is key to finding new treatments for this disease.
| Key Findings | Significance |
|---|---|
| Astrocytes function in matching blood flow to metabolic activity. | Disruption of this process can contribute to hypoperfusion and neuronal damage. |
| Pericytes regulate the blood-brain barrier. | Pericyte dysfunction leads to BBB impairment and leukocyte infiltration. |
| Neurovascular unit dysfunction is correlated with memory deterioration in Alzheimer's disease patients. | Targeting NVU dysfunction may be a promising approach to address cognitive decline in AD. |
"Neurovascular pathways to neurodegeneration in Alzheimer's disease" - Zlokovic B.V., 2011
Conclusion
This review shows how important glial cells are in Alzheimer's disease22. Astrocytes, microglia, and oligodendrocytes all play a big part in the disease. They help cause neurodegeneration by interacting with neurons. This leads to neuroinflammation, trouble with amyloid-beta removal, and problems with the neurovascular unit.
The cerebrospinal fluid amyloid beta42/40 ratio is key in telling Alzheimer's disease apart from other brain disorders22. Aβ43 is often found in the centers of amyloid plaques in Alzheimer's brains22. Knowing these details is vital for finding new treatments for this complex disease.
With Alzheimer's disease affecting about 35 million people worldwide23, research into glial cells is crucial. These cells help make and remove amyloid-beta23. They also affect the neurovascular unit. This research could lead to new treatments and better care for patients23.
FAQ
What is Alzheimer's disease and how prevalent is it?
Alzheimer's disease (AD) is a common type of dementia. It causes memory loss and thinking skills to decline. About 50 million people worldwide have AD or other dementia. This number is expected to rise to over 152 million by 2050.
What are the key pathological features of Alzheimer's disease?
AD is marked by the presence of Aβ plaques and neurofibrillary tangles (NFTs) in the brain. These changes are mainly found in the hippocampus and other brain areas. There's also a strong link between AD and vascular issues.
What is the amyloid cascade hypothesis and how does it explain Alzheimer's pathology?
The amyloid cascade hypothesis suggests how AD develops. It proposes that a protein called Amyloid precursor protein breaks down into Aβ. This Aβ then forms plaques, which harm the brain.
How is vascular dysfunction linked to Alzheimer's disease pathogenesis?
Vascular problems are closely tied to AD. They affect brain metabolism, Aβ removal, and brain health. This leads to memory loss without shrinking the hippocampus.
What is the role of different brain cell types in Alzheimer's disease pathogenesis?
Various brain cells interact in AD. Neurons, astrocytes, microglia, and oligodendrocytes all play parts. Glial cells are key in fighting inflammation, removing Aβ, and keeping the brain's blood vessels healthy.
How do microglia contribute to Alzheimer's disease pathology?
Microglia are vital in fighting AD. They have a receptor called TREM2 that helps them remove Aβ. Without TREM2, microglia can't clear Aβ well, leading to brain damage.
What is the role of astrocytes in Alzheimer's disease?
Astrocytes are important in AD. They can break down Aβ and help brain cells. But, as they age, they make less of the enzymes needed to clear Aβ, which hurts their support for brain health.
How do oligodendrocytes contribute to Alzheimer's disease pathogenesis?
Oligodendrocytes help myelinate brain cells. In AD, they and their precursors don't work well, leading to brain damage. This damage affects how brain cells communicate and learn.
What is the role of the neurovascular unit in Alzheimer's disease?
The neurovascular unit (NVU) is crucial for brain health. Damage to it, along with blood flow issues, worsens AD symptoms. This damage leads to oxidative stress and brain cell death.
Source Links
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- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773743/ - Neuronal Glial Crosstalk: Specific and Shared Mechanisms in Alzheimer’s Disease
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- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084774/ - Microglia communication: Parallels between aging and Alzheimer's disease
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- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540704/ - Amyloidosis is associated with thicker myelin and increased oligodendrogenesis in the adult mouse brain
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