Tag Archives: amyloid

Amyloid-Beta: Villain or Hero in Alzheimer’s Disease? (Podcast)

Last week I was interviewed on Straight from a Scientist, a podcast series where scientists talk about their research for a general audience. In Part 1, which you can listen to here, we had an informal conversation about my research and background. You can now listen to Part 2, a roundtable segment where the host, Connor Wander, and I discuss current topics in Alzheimer’s disease research, including a new look at the physiological roles of amyloid-beta. Enjoy!

 

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Vascular Damage May Affect Progression to Alzheimer’s Dementia

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Guest author: Rachana Tank has a master’s degree in Neuropsychology from Maastricht University in the Netherlands. Her goal is to pursue a PhD in psychology exploring cognitive ageing, where her research interests lie.

As we grow older, we tend to become a little forgetful which is thought to be a normal part of ageing, but when does forgetfulness turn into abnormal ageing? Sometimes even slight but noticeable changes in thinking skills can be symptoms of an underlying issue. Alzheimer’s dementia is a continuous process, a progression taking place over many years, during which individuals experience considerable deficits before reaching clinical dementia. Stages leading up to Alzheimer’s dementia are referred to as predementia stages and are considered to be on the spectrum of Alzheimer’s dementia. In such stages, cognitive deficits are typically experienced as deterioration of memory, attention, and language skills.

Predementia stages can include individuals who self-report a decline in cognitive abilities (subjective cognitive impairments), or experience cognitive impairments that can be diagnosed by standardised testing (mild cognitive impairments). Both of these can, but not always, indicate an initial phase of neurodegeneration that may suggest they are in an early stage of Alzheimer’s dementia.

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The difference between normal brain ageing (purple line) and stages of cognitive decline experienced as part of abnormal brain ageing in dementia. Image source

Individuals with subjective or mild cognitive impairments tend to have a higher incidence of future cognitive decline than the general population and more often show Alzheimer related pathology. However, it is still difficult to predict which individuals in these stages will progress to Alzheimer’s dementia.

Differentiating between those who will progress and who will not is a difficult task. However, biomarkers can be utilised to indicate the presence of Alzheimer’s pathology to detect and diagnose predementia stages. Namely, amyloid protein plaques and neurofibrillary tau tangles are the hallmarks of Alzheimer’s disease, with amyloid pathology being the earliest identifiable change in the brain. Although amyloid and tau have both been fundamental to understanding and estimating the pathological cascade, there is a lot of emerging evidence to suggest that it is not just tau and amyloid in isolation that contribute to progression of Alzheimer’s pathology and subsequent cognitive symptoms.

As evidence indicates there is more to consider than amyloid and tau, recent research, including my master’s research, investigates mixed Alzheimer’s pathology in early stages. Mixed pathology refers to hallmark Alzheimer pathology, such as amyloid and tau, that coexist with additional abnormalities such as vascular disease. Vascular disease is of particular interest in predementia stages as it is the most common disease to coexist with typical Alzheimer pathology early in the disease process.

Vascular disease can be defined as any condition that affects the arteries, veins, and capillaries responsible for carrying blood to and from the heart. Vascular damage can compromise brain health by reducing blood flow to vital areas, leading to loss of neurons. Such damage to the brain affects how well certain areas function, sometimes leading to decreased cognitive abilities such as language difficulties, attention problems or memory issues. There is evidence that vascular disease shortens time to progression when coexisting with traditional Alzheimer pathology. However, the mechanisms by which they may interact is not known.

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Arterial plaques are one example of vascular disease. Image source

My research investigated mixed pathology in 269 memory clinic patients aged 39 or older with subjective or objective cognitive impairments. Levels of amyloid burden and vascular damage were recorded at baseline and at follow-up between 1 and 5 years later. Those who progressed to Alzheimer’s dementia were then compared to those who did not. Vascular damage was assessed using MRI scans, and level of amyloid pathology was determined via cerebrospinal fluid samples.

The results of my research found that Alzheimer’s disease patients with vascular damage had less amyloid in their brains than Alzheimer’s patients who did not have vascular damage. This suggests that vascular damage may worsen the effects of amyloid plaques on cognitive decline and Alzheimer’s. These findings are compatible with other studies that investigated vascular damage in relation to amyloid burden.

Different amounts of amyloid in patients did not show any direct relationship with vascular damage, suggesting that the presence or absence of vascular disease does not influence the presence of Abeta. However, both vascular damage and amyloid pathology increased the risk of progressing to Alzheimer’s dementia significantly, and 93% of individuals who progressed to Alzheimer’s dementia showed abnormal levels of both amyloid and vascular pathology, indicating that both contribute to the development of Alzheimer’s dementia. These research insights help us to better understand early stages and the influencing factors involved. This allows us to develop interventions, for example, promoting cardiovascular health in those at risk by encouraging memory clinic patients to participate in exercise programs.

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Macular Degeneration: Alzheimer’s Disease of the Eye?

Macular degeneration affects more than 10 million Americans, making it the leading cause of vision loss. It occurs when, for reasons that aren’t entirely understood, the central region of the retina (known as the “macula”) begins to deteriorate. The disease is considered incurable and usually occurs in people over the age of 55. Smokers and individuals of Caucasian decent are at an increased risk, as well as anyone with a family history of the disease.

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This animation from the American Macular Degeneration Foundation shows the loss of central vision that occurs with this disease.

Surprisingly, there are many parallels between macular degeneration and Alzheimer’s disease. Though the two conditions may seem unrelated, both are believed to be caused by the buildup of a toxic protein called amyloid-beta. In Alzheimer’s disease, amyloid-beta plaques accumulate in the brain, while in macular degeneration, amyloid-beta forms fatty deposits behind the retina called “drusen.” Plaques and drusen appear to have similar composition of proteins and fats, and utilize the same mechanisms to damage surrounding tissue.

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Diagram of a normal eye and an eye with macular degeneration. Image Source

The similarities between these two diseases don’t end there. Older people with macular degeneration are three times as likely to have cognitive impairment, suggesting that the same processes leading to amyloid-beta accumulation in the retina could also be occurring in the brain. This makes sense, since the retina and the brain are both part of the central nervous system. Additionally, several mouse models of Alzheimer’s disease exhibit amyloid-beta buildup in both the brain and the retina, further cementing the link between the two conditions.

The emerging connection between Alzheimer’s and macular degeneration has several important consequences. If amyloid-beta buildup in the retina could be a sign of a similar process happening in the brain, it raises the possibility that eye exams could serve as a non-invasive method to screen people for Alzheimer’s disease. Clinical trials for this idea are still ongoing, but the early results seem encouraging. These eye exams could potentially allow for earlier Alzheimer’s diagnosis or a lower risk of misdiagnosis.

This relationship also suggests that people with Alzheimer’s disease could be at a greater risk of macular degeneration, or vice versa. If you or a loved one is experiencing dementia, it’s recommended to minimize the risk of macular degeneration by receiving regular eye exams, protecting the eyes from sunlight, and maintaining a healthy diet.

 

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What Naked Mole Rats Can Teach Us About Alzheimer’s Disease

Yes, you read that title correctly. I’m talking about naked mole rats, the burrowing hairless rodents with a face only a mother could love. You might just know them for their strange appearance, but naked mole rats have fascinated scientists for decades due to their extreme longevity. They are by far the longest-lived rodent species, with a maximum lifespan of more than 30 years, compared to only 2 years for your typical mouse. They also are practically immune to cancer, for reasons we don’t entirely understand.

So what does this have to do with Alzheimer’s? Well, another one of the naked mole rat’s strange quirks is that is possesses extremely high levels of amyloid-beta, the toxic protein that is believed to cause Alzheimer’s disease. In humans, amyloid-beta aggregates into sticky plaques in the brain, which can cause a whole host of problems. Amazingly, naked mole rats have even higher amyloid-beta levels than 3xTg-AD mice, which are an Alzheimer’s mouse model genetically engineered to over-produce amyloid-beta. However, the amyloid-beta found in naked mole rats is less sticky and does not tend to form plaques, despite being just as toxic to neurons. Additionally, while amyloid-beta in humans increases as we age, its levels remain constant in naked mole rats. This suggests that amyloid-beta could be harmless (or possibly even beneficial) when it’s present in its non-sticky form. A 2015 report also found that the brains of old naked mole rats look more like what you’d expect to see in a baby animal’s brain, with high numbers of new neurons constantly being formed.

The fact that naked mole rats possess exceedingly high levels of amyloid-beta throughout their lifespan, yet do not develop Alzheimer’s disease, makes them an extremely useful research subject. If scientists can unravel what makes these rodents so resistant to amyloid-beta, we might be able to apply this finding to humans in the form of a treatment for Alzheimer’s disease. So even though they may not be the cutest creatures, you might someday have the naked mole rat to thank for keeping your brain healthy!

Here are some more fun facts about naked mole rats! They have no sense of pain and are nearly blind. They are almost entirely cold-blooded, relying on their environment to regulate body temperature. In order to live underground, naked mole rats have evolved very low rates of breathing and metabolism, and can survive for up to 5 hours in low-oxygen conditions. They live in eusocial colonies similar to ants or bees, with a single queen that produces all the colony’s offspring.

 

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New Alzheimer’s Study Sheds Light on the Mysterious Tau Protein

If you’re a regular reader of AlzScience, you know that Alzheimer’s disease is believe to be caused by two toxic proteins that accumulate in the brain: amyloid-beta and tau. (For more background, see Alzheimer’s Disease: A General Overview.) Recently, it’s been shown that tau is actually a better predictor of Alzheimer’s disease progression than amyloid-beta, suggesting that this mysterious protein might have a larger role in the disease than we once thought.

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Amyloid-beta plaques and tau tangles form toxic clumps in the brains of Alzheimer’s patients. Source

A study published last week in Nature provided deeper insight into tau. The scientists were interested in studying the ApoE gene, which is considered the strongest genetic risk factor for Alzheimer’s (see The Genetics of Alzheimer’s Disease.) Specifically, having two copies of the ApoE4 allele increases your risk of Alzheimer’s by nearly 15 times, and it’s been shown that people with this allele have greater buildup of amyloid-beta in their brains. However, the researchers in this study wanted to see whether ApoE could also affect tau accumulation.

To test this, they used genetically engineered mice that overexpress the tau gene, causing them to develop many of the symptoms of Alzheimer’s. They then tampered with these mice’s genes so that they would also overexpress ApoE4. (Note: Overexpressing the tau and ApoE4 genes means those genes were more active than they normally would be in the mice. Think of it like a light switch stuck in the “on” position.) They found that these mice had more tau in their brains, and also more severe brain shrinkage due to neuronal death.

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This figure from the paper shows brain slices from different mice. The far left panel shows a healthy mouse brain. The next two (representing the ApoE2 and ApoE3 alleles) have slightly more brain atrophy, while the harmful ApoE4 allele causes very severe atrophy. In contrast, the far right brain, which does not express ApoE at all, has relatively little atrophy.

To figure out how ApoE4 might be causing more tau accumulation, the researchers looked at the mice’s microglia, the immune cells of the brain. The microglia overexpressing ApoE4 tended to overreact to infections, releasing high amounts of pro-inflammatory molecules called cytokines. Neurons and other brains cells are very sensitive to cytokines, and high levels might cause them to produce more tau.

Finally, the researchers turned to human research. They used postmortem brain tissues taken from people who had tauopathies, which are diseases caused by accumulation of tau (but not amyloid-beta) in the brain.  The people possessing the ApoE4 allele had more severe neurodegeneration and greater tau buildup in certain areas of the brain.

Overall, this study demonstrates that ApoE4 does not only act on amyloid-beta, but tau as well. It gives strong support to the notion that tau may be as important as amyloid-beta in understanding the pathology of Alzheimer’s disease. In an interview with Science News, Harvard neurologist Dennis Selkoe described this deadly combination of amyloid-beta and tau as a “double whammy.” Yet this study provides hope that future therapies against ApoE4 could be capable of halting both of these toxic proteins at once.

 

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Breakthrough in Alzheimer’s Research: What We Thought About Tau Tangles May Be All Wrong

The main hallmark of Alzheimer’s disease is the accumulation of toxic protein species in the brain. These toxic deposits include senile plaques (made of the amyloid-beta protein) and neurofibrillary tangles (made of the tau protein). In general, recent drug development research for Alzheimer’s has focused on targeting amyloid-beta. This is because previous research suggested that amyloid-beta is responsible for initiating a set of chemical reactions that lead to the phosphorylation of tau. This p-tau (phosphorylated tau) is then more prone to sticking to itself and forming tangles. Thus, the thinking was that if we could get rid of amyloid-beta, tau would no longer form tangles, allowing us to eliminate both toxic proteins at once.

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Plaques and tangles in a normal and Alzheimer’s disease brain.

However, a study published this week in the journal Science may completely change how we think about amyloid-beta and tau. Researchers from Australia looked at enzymes of the p35 family, which are believed to mediate amyloid-beta’s ability to initiate p-tau formation. They focused on a member of this protein family called p35-delta (p35D), after determining that it was the only p35 protein that localized to synapses (the communication junctions between neurons.)

The exciting part of this study came when the researchers generated Alzheimer’s mice that lacked the gene for p35D. These mice experienced exacerbated symptoms of Alzheimer’s disease, including worsened excitotoxicity, memory loss, and premature death. The researchers determined experimentally that these worsened symptoms were dependent on p35D’s ability to create p-tau. In other words, it seems that the presence of p35D (and in turn, the presence of p-tau) was actually protecting the mice from more severe symptoms of Alzheimer’s disease.

This study is big news in the field of neuroscience because it suggests that the formation of tangles by the p-tau protein may be helpful rather than harmful. Whereas in the past scientists have viewed tangles as a harmful side effect of amyloid-beta plaques, these new results indicate that p-tau may actually be a beneficial reaction to the plaques which keeps their toxicity in check. This is consistent with additional data from the study showing that humans with Alzheimer’s disease have reduced expression of p35D. The authors of the paper suggested that a decline in p35D expression, and in turn a decline in p-tau levels, may be a major contributor to the development of Alzheimer’s disease.

Alzheimer’s researchers around the world are very excited about this paper and the ramifications it could have for future studies. Where previously we had been trying to deplete toxic p-tau, this strategy may actually worsen the disease. Rather, perhaps we should be trying to increase levels of p35D and/or p-tau in early Alzheimer’s patients in order to prevent disease progression. It’s possible that this study may also help explain why approximately 1 in 5 elderly adults contain the signature pathology of Alzheimer’s in their brains and yet do not experience any cognitive deficits. Perhaps these individuals benefit from higher expression of p35D which helps fight of the toxicity of amyloid-beta. Future studies will investigate whether this is indeed the case.

As always, we must interpret these results with caution. Since this study was based in mice, a lot of additional research will be needed to determine whether similar neurochemical pathways occur in humans and, if so, whether these can be utilized to design a preventative treatment for Alzheimer’s. Only time can tell how far-reaching the impacts of this study will be.

 

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