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The Alzheimer’s Hypothesis

Introduction

Alzheimer’s disease was first discovered in 1907 in a 51 year old woman by the German physician A. Alzheimer. One of the first changes noticed was an eruption of jealous feelings towards her husband. It wasn’t long before symptoms of rapid memory impairment were observed. The impairments prevented her from finding her way out of her home, She hid herself, she would drag objects to and fro, and occasionally screamed because she believed people were out to kill her.

When she was institutionalized her gestures would show a complete helplessness. As common in most Alzheimer’s patients, she was disoriented as to time and place. At times she would state that she didn’t understand anything, felt confused, and totally lost. When the doctor came in to see her she would consider it as an official visit and would apologize for not having finished her work. Other times she would be terrified and start to yell that the doctor wanted to operate on her. Other times she would send him away in complete indignation uttering phrases indicating that she was afraid that the doctor wanted to damage her woman’s honor. At times she would become completely delirious , dragging her blankets and to and fro, calling for her husband and daughter, and seeming to experience auditory hallucinations. She would often scream for hours and hours in a horrible voice. Mental regression advanced quite steadily. After four and a half years of illness the patient finally died.

Alzheimer performed a postmortem examination of the woman’s brain. He paid special attention to changes in the “neurofibrils,” fibers in the cytoplasm of a nerve axon — elements of the cytoskeleton that can be stained by a silver solution.

The Bielschowsky silver preparation showed very characteristic changes in the neurofibrils. Looking inside an apparently normal-looking cell, however, one or more single fibers became observably prominent through their striking thickness and specific impregnability. At a more advanced stage many many fibers arranged in parallel showed the same changes. Over time they formed dense bundles and gradually advanced to the surface of the cell. The cell and nucleus would eventually disappear, leaving only a tangled bindle of fibrils where the neuron once was.

Since these fibrils can be readily stained with certain dyes, a chemical transformation of the fibril substance must have taken place. This might be why the fibrils survived the destruction of the cell. The transformation of the fibrils seems to go hand in hand with the storage of an as-of-yet not closely investigated pathological byproduct of neuronal metabolism. Such alterations were found in about one-quarter to one-third of all the neurons in the cerebral cortex. Numerous neurons, especially in the upper cell layers, had completely disappeared.

The number and distribution of neurofibrillary tangles, what are commonly known as the “tombstones” of dead and dying neurons, are correlated with the severity of the symptoms in Alzheimer’s disease.

Phase1

What is the purpose of beta-amyloid?

Alzheimer’s disease causes impairment with memory, thinking, and behavior. Alzheimer’s affects 5.5 million people age 65 and older and approximately 200,000 individuals under the age 65. Alzheimer’s disease is the 5th leading cause of death in the United States. The root cause of Alzheimer’s is still unknown. There are several hypothesis that attempt to explain it. This article focuses on the research being done in a joint effort between a team from Harvard University being led by Rudolf Tanzi and Robert Moir at Boston Massachusetts General Hospital.

Tanzi and Moir investigated the development of Alzheimer’s disease in animals and found the development of amyloid plaques is not unique to humans. 70 percent of vertebrates share certain sequences of particular amino acids in human beta-amyloid. Moir believes because this sequence is shared so widely and has not changed over time that it must be doing something very important. Moir discovered that the antimicrobial peptide LL37 acts as one of the brain’s defenses against microbes alongside beta-amyloid.

In order to test this hypothesis, the team injected the brains of mice that were bred to develop Alzheimer’s plaques comparable to the way humans do with bacteria. Overnight, the mice produced plaques. Tanzi discovered that each plaque had a single bacterium in it. A single bacterium can induce an entire plaque.

25 May 2016

New Scientist

Science Translational Medicine 25 May 2016:

Vol. 8, Issue 340, pp. 340ra72

DOI: 10.1126/scitranslmed.aaf1059

Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease

Full Abstract

Phase 2

The Role of Sleep on the Brian’s Filtration System

Lulu Xie and team recently uncovered one of the key functions of sleep. The team compared 2 arousal states in the mouse, sleeping and awake, using state-of-the-art in vivo two-photon imaging. The researchers found that metabolic waste products of neural activity were cleared out of the sleeping brain at a faster rate than during the awake state. Like the accumulation of beta amyloid plaques, sleep is a cross-species phenomenon.

The study by Xie et. al reports that the critical function of metabolic homeostasis is dependant on sleep. The team utilized real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice. The experiment found a 60 percent increase in the interstitial space in association of natural sleep or anesthesia. This resulted in a noticeable convective exchange of cerebrospinal fluid and interstitial fluid, which are found in the spaces between the blood vessels and surrounding cells.

Thus as a result convective fluxes the rate of β-amyloid clearance during sleep. Hence, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate during our waking hours.

Sleep Drives Metabolite Clearance from the Adult Brain

Science 18 Oct 2013:

Vol. 342, Issue 6156, pp. 373–377

DOI: 10.1126/science.1241224

Full Abstract

In a separate study Ehsan Shokri-Kojori and team published a study on April 9 2018 showing that just 1 night of sleep deprivation builds β-Amyloid within the brain.

PNAS April 24, 2018 115 (17) 4483–4488

Full Abstract

On September 5th of this year The Sleep Research Society came out with a report that collaborates with the data suggesting just how important the role of sleep is to prevent Alzheimer’s disease. The Baltimore Longitudinal Study of Aging, conducted by Adam P Spira et al showed that those who experienced excessive sleepiness during normal waking hours were nearly three times more likely to have brain deposits of beta amyloid than those who didn’t.

PET scan of a human brain with Alzheimer’s disease

Sleep, zsy152

Published: 05 September 2018

Full Abstract

The accumulated evidence above shows that Beta-Amyloid are part of the brain’s ancient immune system . The evidence also indicates that the buildup of Beta-amyloid plaques occurs when it’s not flushed out. Many researchers, including Rudolf Tanzi and Robert Moir believe that it is the plaques that cause the damage to the brain.

Phase 3

The fIltration System of the Brain

The re-discovery of cellular membranes around the brain known as meningers has a network of lymphatic vessels that drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. This lymphatic system was first discovered in 1787 (Mascagni, P. Vasorum lymphaticorum corporis humani historia et ichnographia) and was rediscovered by Da Mesquita et al.

Their research showed that meningeal lymphatics play a central role in brain health and disease by helping to maintaining both cognitive function and proteostasis.

The purpose of the lymphatic system in the body is to drain tissue of interstitial fluid that houses cellular debris and toxic chemicals. A rich protein-fluid called lymph is formed by interstitial fluids which circulates through the lymphatic system before returning to the blood. Lymph is filtered through the lymph nodes. Lymph nodes are responsible for initiating immune responses when foreign particles are detected.

Because the brain does not have its own lymphatic vessels it utilizes the interstitial fluid (ISF) along the walls of blood vessels to transport waste and proteins from the parenchyma to reach the cerebrospinal fluid that circulates through the meninges. The transvascular process is the process in which metabolic waste products, proteins, and other molecules in these fluids are removed from the brain by being transported along the walls of blood vessels, which crosses the blood-brain barrier. To what extent, if any, the meningeal lymphatic vessels were also involved in waste clearance is still unknown.

To verify the critical role of the meningeal lymphatic vessels Da Mesquite et. al injected a drug designed to damage the vessels into one of the three principal openings in the subarachnoid space between the arachnoid and pia mater layers of the meninges surrounding the brain, collectively referred to as the cisterna magna. In order to track the CSF they injected a fluorescent tracer molecule. This provided insight as to where the fluid goes in mice lacking meningeal lymphatic vessels. Da Mesquite et. al noted that the the tracer did not travel deep into the cervical lymph nodes in mice lacking meningeal lymphatic vessels. Injecting high concentrations of a tracer into the CSF can cause the diffusion of a tracer into the brain along blood vessels as shown by previous work — but this too was also reduced. The researchers used different tracers, surgically closing off drainage to the deep cervical lymph nodes; and examined mice with impaired lymphatic vessel development . The authors were able to confirm through these various methods the results by doing so.

The authors also noted that deficits within spatial orientation and memory were a result of meningeal lymphatic destruction.

Another interesting finding by the researchers was a change in gene expression within the hippocampus, a substructure crucial to memory and spatial orientation.

The gene expression resembled those previously observed in neurodegenerative disorders. The accumulated evidence by these experiments suggests collectively that the drainage of brain ISF and CSF by meningeal lymphatics is critical to proper function of cognition within the brain.

These findings present an interesting question: where exactly did the tracers go? One study (https://onlinelibrary.wiley.com/doi/abs/10.1038/icb.1951.30) suggests that tracers injected into the cisterna magna are transported primarily in the blood and that the lymphatic system is only secondary. To reveal whether the impairment of meningeal lymphatics can lead to a shift in the pathways responsible for controlling brain proteostasis the simultaneous measurements of tracers movements meningeal lymphatics, other lymphatic vessels, (for example the neck) and the blood may give insights into whether there’s an increase in the transvascular removal of waste products across the blood-brain barrier and/or their drainage into the venous system in the meninges.

The next observation by Da Mesquita’s team was a decrease in the diameter and coverage of meningeal lymphatic vessels through induced aging. The researchers also observed a decrease in drainage of tracers from the ISF and CSF into deep cervical lymph nodes. The signaling of the pathway involving vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 promotes lymphatic vessel growth in mice. Likewise when the pathway involving endothelial growth was damaged it caused a loss of meningeal lymphatic vessels. Moreover the authors showed that there was an increase diameter of meningeal lymphatic vessels by providing treatment VEGF-C, improving lymphatic drainage as a result. Consistent with the accumulated research, Da Mesquita et al. showed that the drainage of CSF tracer could be restored into deep cervical lymph nodes by the local delivery of the vegf-c into the cisterna of old mice with a viral vector . This resulted in the restoration of spatial orientation.

The accumulation of amyloid-β protein within the brain, a hallmark of Alzheimer’s disease, causes age related impairments in the transvascular clearance of waste. The effects of of ablating the meningeal lymphatics in two mouse models of Alzheimer’s disease, in which amyloid-β protein is produced in neurons and secreted into the ISF was investigated by Da Mesquita and team. The results showed that ablation led to the accumulation of amyloid-β protein in the meningenges. The authors also noted to the potential relevance for humans by showing that amyloid-β had accumulated in meningenges of people who had Alzheimer’s disease as well.

When amyloid-β protein deposition in the brain parenchyma first became apparent, Da Mesquita and colleagues discovered that the two mouse models did not exhibit any apparent structural or functional changes in the meningeal lymphatics at the time. Cognitive impairment could not be prevented in either model using viral delivery vegf-c, which points to another disruption in another clearance pathway the early amyloid-β deposition and cognitive impairments in these two models-most likely the transvascular clearance. More than likely an increased burden is placed upon meningeal lymphatic system due to the gradual deterioration of transvascular-clearance routes through aging. Faulty lymphatic drainage of amyloid-β and other proteins from the ISF and CSF may be caused when the capacity of the lymphatic system is reached. This gives strong evidence to suggest that there is a very delicate relationship between meningeal lymphatics and blood vessels in the regulation of proteostasis in the brain.

In order to open new directions for research into cognition, neurodegeneration, and Alzheimer’s disease, the improvement of our understanding of waste clearance pathways from the brain, how the ISF and the CSF drain into the meningeal lymphatics, and how these lymphatic vessels interact with the blood vessels at the blood-brain barrier is vital. The potential of improving clearance with meningeal lymphatics to rebuild brain proteostasis, and may lessen amyloid-β protein deposition have been shown by Da Mesquita et al. to rely upon the local growth of lymphatic vessels. Whether or not the improvement of the impaired function of blood vessels due to aging, and whether enhancing clearance at the blood-brain barrier can improve lymphatic drainage function, remains to be to determined.

Nature 25 July 2018

A lymphatic-waste disposal system implicated in Alzheimer’s Disease

Naturevolume 560, pages185–191 (2018

Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease

Full Abstract

The accumulated evidence shows that Beta-amyloid may prove to be beneficial in killing off microbes, but also that proper rest is needed to activate the filtration system of the brain to consistently flush out these neurotoxins before they cause impairment or disease . Further research into the prevention of age-related damage to the brain’s lymphatic system may offer clues as to how we can prevent cognitive decline of age-related diseases. Ideally this will be done with protective mechanisms the brain already has in place.

Journal of Alzheimer’s Disease — Volume Pre-press, issue Pre-press, vol. 65, no. 2, pp. 659–682, 2018

Accepted 5 July 2018

Published: 21 August 2018

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Full Abstract

Further analysis of these key factors could pave the road to ending Alzheimer’s and other age-related diseases.

Nicholi Avery, [email protected]

Adam Alonzi, [email protected]

For the first time ever researchers have had a breakthrough in creating a cocktail of drugs that caused new neurons to grow in the brains of mice.

In my last article I gave a detailed account on the debate of neurogenesis. While some neuroscientists claim that neurogenesis takes place within the adult mammalian human brain other researchers contest that idea claiming that new neurons stop developing at a very young age. Whichever side of the debate you are on one thing remains certain, that there are neurological diseases that leave negative impacts on cognitive function. This has left researchers looking for various ways to treat Alzheimer’s, Parkinson’s, and other brain damage.

While the brain is incredibly complex and past research has failed to offer much hope for Alzheimer’s disease, Hongkui Deng at Paking University Health Science Center in China may finally be able to change that.

For the first time ever researchers have had a breakthrough in creating a cocktail of drugs that caused new neurons to grow in the brains of mice.

What this cocktail does when injected into the brain is it hijacks the astrocytes into behaving like new neurons. This is significant for a number of reasons. One important detail about astrocyte cells is that they can survive after a stroke while regular neurons die. Another important detail is that there are 10 times more astrocytes in the brain than neurons. That means that there are 1 trillion glia cells within the brain. So not only are they more resilient than neurons they outnumber them too.

Deng and his team of researchers have found that when the cocktail is injected into the brains of mice that it effectively gives the cell a new identity by erasing its old one and giving it a new one. Not only did the cells change shape but they showed change in gene activity too.

The results were substantial. While it remains speculative as to how closely the cells resemble normal neurons, around 80 to 90 per cent of the astrocytes started to resemble neurons and even mimicked their behavior by electrical signals the same way regular neurons do.

They are unlikely to be a 100 percent match” Deng stated. “But the treatment was safe and none of the mice developed any health problems”.

Matthew Grubb at King’s College London states that “if it holds up it’s absolutely amazing, and has a lot of potential applications and exciting consequences. If you’ve got a degenerating brain, for example in Alzheimer’s disease, and you could get the brain to regrow neurons itself, it would be a huge step forward.”

The next step for the researchers will be to test the cocktail in mice that have had a stroke. The hope is that the cocktail will cause the astrocytes to behave as neurons and help the mice recover.

While Grubb admits it is difficult to predict the effects of the treatment in humans, if it works in mice then it offers new hope for those who suffer from neurodegenerative diseases such as Alzheimer’s or Parkinson’s. While it is unlikely to bring back lost memories Grubb thinks it might restore the ability to create new ones.

Even though the research is promising there still remain challenges as Roger Barker at the University of Cambridge points out. The sheer numbers of cells lost in a neurodegenerative disease is something to consider. “In Parkinson’s, a quarter of a million cells are lost from either side of the brain. Currently Barker is conducting clinical trials of implants of brain tissue taken from aborted fetuses as a treatment for Parkinson’s.

Another challenge is to distinguish the types of neurons the drugs will make. As Grubb points out, if you make too many of the type of neurons that excites their neighbors you end up triggering epilepsy. Grubb also points out that different brain disorders effects different types of neurons which is another reason why we need to be capable of distinguishing them. The neurons that die from Parkinson’s are the neurons that create the chemical dopamine for example.

Another example is balancing the risks for rewards. As Grubb points out “you’d have to have extremely good control over what cells you’re programming, where they’re going to go, and which cells they’ll connect to. If the treatment were to be used to boost grey matter, for example, this could provide a way to improve skills like memory. However, too much grey matter has been linked to causing people to be being easily distracted.

While the research is definitely groundbreaking it is still in its early stages. Hopefully in the near future it will offer treatments to those who need them.

New Scientist

From CLUBOF.INFO

The increasing detail at which human brains can be scanned is bringing the possibility of mind-reading appliances closer and closer. Such appliances, when complete, will be non-invasive and capable of responding to our thoughts as easily as they respond to keys on a keyboard. Indeed, as emphasized in the Lifeboat Foundation’s 2013 publication, The Human Race to the Future, there may soon be appliances that are operated by thought alone, and such technology may even replace our keyboards.
It is not premature to be concerned about possible negative outcomes from this, however positive the improvement in people’s lifestyles would be. In mind-reading appliances, there are two possible dangers that become immediately obvious.

Danger 1: “Thought police”

Brain-machine interfaces have many possibilities that deserve to be explored by science. However, there are also potentially dystopian threats presented by this technology. Even technologies like personal computers, which were seen as liberating to the individual and not aligned with powerful governments, have also become windows that regimes can use to spy on their citizens.

If hardware eventually allows words to appear on screens simply because of a thought, and the appliances are still vulnerable to hacking or government pressure, does this mean minds can be read without consent? It is very likely that any technology sensitive enough to respond to our thoughts could be programmed by a regime to intercept our thoughts. Even if our hardware was not originally designed to intercept thoughts on behalf of the authorities, the hardware would already meet the requirements for any program written to intercept thoughts for policing and political repression.

The potential negative consequences of mind-reading technology are equivalent to those of “uploading”, the futuristic concept of transferring one’s mind to computers as popularized by Singularitarians, usually following the ideas of Ray Kurzweil. There is a real threat that a technological singularity, as depicted in Kurzweil’s The Singularity is Near, could strengthen a flawed social system by giving the authorities the intrusive ability to monitor what it sees as deviant or threatening thought.

Danger 2: Accidents

It may be that manual or verbal control, still depicted in science fiction as gifts that will be with us for many centuries and taken with humanity’s distant descendants to the stars, are just more practical than mind-reading. Even when limited to practical uses like controlling a vehicle or appliance, mind-reading may simply be destined to take away convenience rather than create convenience for the vast majority of its customers.

Even if driving a car by thought can be made safe, the use of aircraft or weapons systems via mind-reading would certainly be more problematic. When the stakes are high, most of us already agree that it is best not to entrust the responsibility to one person’s thoughts. By not using the body and voice when performing a task, and by not allowing others to intervene in your actions, the chances of an accident are probably always going to be raised. Although we like to think of our own brains as reliable and would probably be eager to try out mind-reading control over our vehicles, we do not think of others peoples’ brains that way, and would be troubled by the lack of any window for intervention in the other person’s actions.

Possible accidents when piloting a complex machine like a helicopter or manning a dangerous weapon may be averted by an experienced hand preventing someone from taking the wrong action. Considering this, old-fashioned manual controls may already be destined to be superior to any mind-reading controls and more attuned to the challenges faced by humans. We evolved to talk and physically handle challenges. Given this fact, removing all the remaining physical challenges of performing a task may only complicate your ability to perform effectively, or result in a higher tendency to err or take rash actions by subverting the ability of others to challenge you as you act.

Recommendation: we should avoid strengthening an undesirable social system

I hope that these objections to mind-reading may be proven invalid, with time. It is certainly likely that some people, such as those with physical disabilities, are going to rely on improvements in mind-reading technology to restore their lives. However, there has been, and continues to be, a very definite danger that a flawed social system and government are going to seek out technologies that can make them more and invulnerable, and this is one such technology. Any potential avenue of invulnerability of governments against their critics is unacceptable and should be challenged, just as the present excess in surveillance has been challenged.

It is important to keep reiterating that it is not the technology itself that is the source of a threat to humanity, but the myopic actions of the likely operators of that technology. Given the experience of government mass espionage, which began without the knowledge or consent of the public, concerns about other unannounced programs exploiting communication technology for “total information awareness” (TIA) are justified.

By Harry J. Bentham - More articles by Harry J. Bentham

Originally published on April 22 in Dissident Voice

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