Open Questions: Neurodegenerative Diseases
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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.
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.
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.
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 news article, subtitled
"Researchers remain optimistic about a vaccine against Alzheimer's."
-
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.
-
Hope for an Alzheimer's Vaccine
- December 2000 Scientific American new article about
the possibility of a vaccine for Alzheimer's disease.
-
Soothing the Inflamed Brain
- June 2000 Scientific American story on the possible
use of anti-inflammatory drugs to control 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.
-
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.
-
Peeling Plaque
- May 2002 Scientific American Technology & Innovation
article about hopes for developing a vaccine to reverse
Alzheimer's disease.
-
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.
-
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.
-
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.
-
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.
- Anxiety and Alzheimer's
Nicole Branan
Scientific American, October 2007
-
-
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.
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Copyright © 2002 by Charles Daney, All Rights Reserved