Open Questions: Neurodegenerative Diseases

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Introduction

Beta amyloid

Remaining questions


Recommended references: Web sites

Recommended references: Magazine/journal articles

Recommended references: Books

Introduction

Although Alzheimer's disease is not something new in the way that AIDS is, recognition of it as a distinct pathology is relatively recent. The disease is named after a German neurologist, Alois Alzheimer, who in 1906 in the course of an autopsy first observed certain abnormalities in the brain of the deceased. These abnormalities are now what are referred to as "plaques" occurring between nerve cells in the brain and "tangles" within the neurons themselves.

Of course, long prior to Alzheimer's discovery, the characteristic external symptoms -- loss of memory, disorientation, inability to care for oneself -- had been recorded in medical literature as far back as the Greeks. A syndrome of this kind was usually referred to simply as "senility" or "dementia". We now know that senility/dementia can result from a variety of causes, of which the physical symptoms that Alzheimer discovered occur in only a subset of cases. (Other causes include stokes, trauma to the brain, or just the normal age-related loss of neurons.)

As recently as 15 years ago general recognition of Alzheimer's disease as a specific pathology was much lower, it was considered impossible to distinguish from other dementias except at autopsy, and nothing was known of its cause or mechanism of action. Much of that has now changed -- but a great deal still remains unknown.

The most obvious "cause" of the disease is the excessive death or disablement of neurons in certain parts of the brain -- especially the hippocampus (which is involved with memory) and the cerebral cortex (which is involved with reasoning, memory, and other cognitive skills). It turned out that many of these neurons were of the type known as "cholinergic" becuase they use the neurotransmitter acetylcholine. Acetylcholine is broken down normally in the brain by an enzyme known as acetylcholinesterase. However, when cholinergic neurons are depleted, mental function can be improved by conserving acetylcholine, and this can be accomplished by certain drugs that have became available in the last ten years (tancrine and donepezil) and which block acetylcholinesterase.


Beta amyloid

Unfortunately, when cholinergic neurons have degenerated beyond a certain point, these drugs become ineffective. So the question is, what actually causes the abnormal neural degeneration? Most signs point to the so-called plaque material as the chief culprit, either because it is directly toxic to neurons or else because it induces a destructive response from the body's own immune system. One of the other key facts, which was discovered only in 1984, is that the plaque consists of a peptide (i. e. an amino acid polymer) called beta amyloid.

So where does beta amyloid come from? It turns out that it is a fragment of a protein which is embedded in the cell membranes of normal neurons. This protein is called, rather uncreatively, the beta amyloid precursor protein (BAPP for short). BAPP sticks out of the cell membrane like a whisker or blade of grass, but it is still a mystery what it is actually there for. In addition, there are three related enzymes which snip off parts of the BAPP. Two of these, called alpha secretase and beta secretase, make the first cut at a certain point -- not the same for the two enzymes -- on the part of BAPP which sticks out from the neuron. Then a third enzyme (gamma secretase) snips off a further fragment of BAPP back to the cell membrane. It is this second fragment which is the problem. The fragment which results from a cut by alpha secretase is a peptide known as p3, which appears to be harmless. But when beta secretase makes the first cut, the result is the dreaded beta amyloid peptide. (As it happens, there are two forms of beta amyloid which can result. One has 40 amino acids and seems to be harmless. The other has 42 amino acids, and seems to be the true villain.)

Given all this, beta and gamma secretase look like natural drug targets. Inhibiting either one of them would block production of beta amyloid (either form). This avenue is being aggressively pursued. Unfortunately, we still don't know what the biological function of either BAPP or the secretase enzymes actually is. (The gene for beta secretase was identified only in 1999, and the genes for the other secretases are still undiscovered.) Consequently, blocking these enzymes could have harmful side effects. These are just some of the questions which are still open.


Remaining questions

But there are plenty of other open questions too. Alzheimer's is (like cancer) not at all a simple disease. For one thing, prsence of the plaque material seems to be a necessary but not sufficient condition for the disease. "Normal" brains have been found at autopsy to contain plaque, even though the deceased didn't have the external symptoms of dementia. There seems to be little correlation between the amount of plaque present and the severity of symptoms (if any).

Another set of questions revolves around the neurofibrillary "tangles" which are found inside the neurons of most Alzheimer's victims. They are known to consist of a protein called tau. Tau is known to bind with another protein called tubulin, which makes up the microtubles of all cells, including neurons. Microtubles are absolutely essential for normal cellular function, so anything that interferes with their operation would be very harmful. Obvious questions include: What is the normal function of tau protein? What causes it to form tangles? Is the presence of plaque somehow involved? Are the tangles in fact harmful and implicated in the Alzheimer's symptoms? We don't know the answers to any of these.

A final set of questions involve hereditary and environmental factors which might trigger Alzheimer's disease. It is known that the disease can be both "familial" (occurring frequently in a given family, hence hereditary) and non-familial (where the disease strikes individuals without touching close relatives). Further, in familial Alzheimer's, sometimes the disease has an early onset (in the 50s) while sometimes it is much later. What accounts for such variations? And what about environmental factors, such as exposure to aluminum, which have from time to time been suspected of complicity?

Obviously, without many more answers to these questions, treatment of Alzheimer's will be a shot in the dark. It is such a complex disease that there are probably a number of points in the process that can be interrupted to prevent the harm from occurring. (Inhibit plaque formation or remove existing plaque in various ways, interfere with whatever process actually casues neuron death, etc.) But until we actually understand the causal chain much better, we risk unknown side effects, or at least set ourselves up to explore many blind alleys.


Recommended references: Web sites

Site indexes

Galaxy: Alzheimer's Disease
Categorized site directory. Entries usually include descriptive annotations.
Galaxy: Parkinson's Disease
Categorized site directory. Entries usually include descriptive annotations.

Sites with general resources: Alzheimer's disease

MedlinePlus: Alzheimer's Disease
Links to various kinds of information, from MedlinePlus
Alzheimer's Association: Physicians and Care Professionals
This part of the Alzheimer's Association site provides some information on diagnosis and treatment of the disease for physicians and health care professionals.
Alzheimer's Disease Education & Referral Center
Site sponsored by the U. S. National Institute on Aging, mostly with general information, but with a good section called Unraveling the Mystery that gives scientfic information on the disease and research programs. There is also general inofmation, and information on causes, symptoms, diagnosis, and treatment.
Alzheimer's Disease Research Information
Pages provided by Elan Corporation containing a list of some published research articles and other information on the disease.
Alzheimer's Society
"The Alzheimers Society is the UKs leading care and research charity for people with dementia, their families and carers." Useful pages include facts about dementia, research into dementia, and how is dementia diagnosed?.
Alzheimer's Research Trust
"The Alzheimer's Research Trust is the leading Alzheimer's research charity in the UK. The Trust funds UK research into the causes, treatment and prevention of Alzheimer's disease and related dementias, including vascular dementia, dementia with Lewy Bodies and fronto-temporal dementia." The site has a good general information page.

Sites with general resources: Parkinson's disease

Medline Plus: Parkinson's disease
General article on causes, symptoms, and treatment, from Medline Plus. The same site has another page with recent news, external links, overviews, and other tutorial information.
Parkinson's Disease Society
UK charitable organization that promotes research on the disease and provides assistance to people with Parkinson's. The site contains a number of pages with general information.

Surveys, overviews, tutorials: general

Category: Neurology
Topic category from Wikipedia.

Surveys, overviews, tutorials: Alzheimer's disease

Alzheimer's disease
Article from Wikipedia.
Encyclopedia of Life Sciences: Alzheimer's Disease
Excellent scientific article from the online Encyclopedia of Life Sciences.
Impact of Neuroprotection on Incidence of Alzheimer's Disease
Research paper that shows increasing "cognitive reserves" through education or other intellectual activity can decrease incidence of Alzheimer's disease.
Alzheimer's Disease
A ScienceWeek "symposium" consisting of excerpts and summaries of articles from various sources.
Alzheimer's Disease: Molecular Mechanisms
Detailed survey by Ben Best.
Alzheimer's Disease Fact Sheet
General information on Alzheimer's disease, provided by the Alzheimer's Disease Education & Referral Center.
Alzheimer's disease
Quick summary of basic facts about Alzheimer's disease, from the BBC.
Alzheimer's Disease
December 2006 Scientific American Sidebar about the experimental Alzheimer's drug Alzhemed.
Alzheimer's Vaccine?
March 2005 Scientific American sidebar note about a possible vaccine for Alzheimer's disease.
Downsized Target
May 2004 Scientific American In Depth article, subtitled "A tiny protein called ADDL could be the key to Alzheimer's".
Brain Not Inflamed?
October 2003 Scientific American In Depth article, subtitled "Alzheimer's may not be an inflammation after all."
Peeling Plaque
May 2002 Scientific American Technology & Innovation article about hopes for developing a vaccine to reverse Alzheimer's disease.
Toward Early Diagnosis of Alzheimer's Disease
August 2001 Scientific American In Depth article that discusses recent research on detecting Alzheimer's disease at an early stage using brain scans.
Molecule Helps Brain Cells Clear Alzheimer's Plaques
May 2001 Scientific American news article about how microglia cells may help clear amyloid plaques.
Cleaning Alzheimer's Plaques
March 2001 Scientific American news article about a new technique to remove amyloid beta plaques from mouse brains.
Gene Therapy for Alzheimer's
February 2001 Scientific American Technology & Innovation article about using gene therapy to restore axons that have atrophied as a result of age.
Hope for an Alzheimer's Vaccine
December 2000 Scientific American news article about research supporting the idea that amyloid beta plaques are responsible for Alzheimer's disease, and that a vaccine might be able to stimulate the immune system to eliminate the plaques.
More Alzheimer's Genes
December 2000 Scientific American news article about new studies that seem to have identified genes that increase risk of developing Alzheimer's disease.
New Gene behind Alzheimer's Disease?
September 2000 Scientific American news article about the relation of the apolipoprotein E-4 gene to Alzheimer's disease. 4
Soothing the Inflamed Brain
June 2000 Scientific American story on the possible use of anti-inflammatory drugs to control Alzheimer's disease.
Sedentary Off-hours Link to Alzheimer's
March 2001 Science News article about a link between Alzheimer's disease and either physical or mental inactivity.
Possible Alzheimer's Vaccine Seems Safe
July 2000 Science News article about an experimental vaccine for Alzheimer's disease.
A Vaccine for Alzheimer's Disease
July 1999 Science News article about an experimental vaccine for Alzheimer's disease.
Evidence that Alzheimer's Protein Switches on Genes
July 6, 2001 research announcement.
Alzheimer's - Triggering Enzyme Identified
May 18, 2000 research announcement.
Untangling a Link Between Normal Protein Folding and Alzheimer's Disease
December 22, 1999 research announcement.
Researchers Find Early Trigger of Brain Cell Death in Alzheimer's Disease
December 8, 1999 research announcement.
Avoid Alzheimers... eat less
January 1999 news article about research showing that rats on a calorie-restricted diet suffered less from toxins that simulate brain damage.
Is there any proof that Alzheimer's disease is related to exposure to aluminum?
July 1997 answers to a Scientific American Ask the Experts question.

Surveys, overviews, tutorials: Parkinson's disease

Parkinson's disease
Article from Wikipedia.
New Movement in Parkinson's
July 2005 Scientific American report, subtitled "Recent genetic and cellular discoveries are among the advances pointing to improved treatments for this increasingly common disorder."
Parkinson's Disease
A ScienceWeek "symposium" consisting of excerpts and summaries of articles from various sources.
Pesticides and Parkinson's
November 2000 Scientific American news article about a study that shows the pesticide rotenone causes Parkinson's symptoms in rats.
Coffee's Ties to Parkinson's
November 2000 Scientific American news article about a possible inverse correlation between coffee drinking and Parkinson's disease.
An alternate approach to Parkinson's
June 2000 news article from Science News about use of dopamine agonists to treat Parkinson's disease.
Caffeine fix may reduce risk of Parkinson's
May 2001 news article about mouse experiments that showed an effect of caffein in blocking A2A receptors, which may play a role in Parkinson's disease.
Mouse catches Parkinson's disease
February 2000 news article about development of a mouse that expresses α-synuclein, as a model for Parkinson's disease.


Recommended references: Magazine/journal articles

Secrets of Aging
Carol Barnes
The Scientist, September 2011
What does a normally aging brain look like? Are diseases of aging such as Alzheimer's inevitable?
Memories Can't Wait
Laura Sanders
Science News, March 12, 2011
Researchers rethink the role of amyloid in causing Alzheimer's.
The Genes of Parkinson's Disease
Bobby Thomas; M. Flint Beal
The Scientist, February 2011
The minority of Parkinson's cases now known to have genetic origins are shedding light on the cellular mechanisms of all the rest, bringing researchers closer to a cause - and perhaps a cure.
Neuron Killers
Tina Hesman Saey
Science News, August 16, 2008
Misfolded, clumping proteins evade conviction, but they remain prime suspects in neurodegenerative diseases.
Anxiety and Alzheimer's
Nicole Branan
Scientific American, October 2007
Predicting Parkinson's
Carolyn Gramling
Science News, May 13, 2006
Researchers search for early warnings in the brain.
Shutting Down Alzheimer's
Michael S. Wolfe
Scientific American, May 2006
Attacking Alzheimer's
Damaris Christensen
Science News, November 3, 2001, pp. 286-287
The importance of other effects -- such as "tau tangles" -- in the development of Alzheimer's disease may be comparable to that of the well-known beta-amyloid plaques.
[References]
An End to Alzheimer's?
Ken Garber
Technology Review, March 2001, pp. 70-77
A lot is now known about what goes wrong to cause Alzheimer's disease. This knowledge has led to the development a variety of experimental drugs that offer hope for a successful treatment of the disease.
Statins Take On the Brain
John Travis
Science News, February 10, 2001, pp. 92-93
Cholesterol-lowering drugs known as statins have provided a major improvement in the treatment of cardiovascular disease. The are now being investigated for treatment of Alzheimer's disease.
Piecing Together Alzheimer's
Peter H. St George-Hyslop
Scientific American, December 2000, pp. 76-83
The mystery of Alzheimer's disease at the molecular level appears to be rapidly clearing up. The new understanding suggests there may be a variety of approaches to treatment.
Understanding Parkinson's Disease
Moussa B. H. Youdim; Peter Riederer
Scientific American, January 1997, pp. 52-59
The proximate cause of Parkinson's disease appears to be destruction of dopamine-producing cells in the brain region known as the substantia nigra. It is less clear what causes the death of those cells, but the action of free radicals is one suspect.


Recommended references: Books


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