How is inflammation involved in Alzheimer's disease? Is it cause or
effect? How does the amyloid protein that is found post mortem relate
to inflammation? Which anti-inflammatory drugs might work and why?

Hello, nish!

A study in 1997 showed that non-steroidal anti-inflammatory drugs
(such as ibuprofen) helped prevent the development of Alzheimer's
disease, and it was assumed that the drugs were fighting inflammation.
More recent research is showing that it's in fact not the
anti-inflammatory action of  the NSAIDs, but that the drugs are
actually inhibiting production of the Amyloid-beta 42 protein which is
found in Alzheimer's patients and is what kills the patient's brain
cells. However, currently available NSAIDs can have severe
side-effects, including bleeding into the liver, so they are not
curerntly recommended for long-term use.

Some interesting articles are:

http://www.alzheimers.org/nianews/nianews10.html
See Neurology 48(3): 626-632, March 1997, for the research report

Painkillers hold clues to Alzheimer’s
http://senrs.com/painkillers_hold_clues_to_alzheimers.htm

Long-term use of NSAIDs reduces risk of Alzheimer's
http://www.alzheimers.org.uk/news_events/researchnews.html#nsaids

I hope this has answered your questions!

---

Request for Answer Clarification by nish-ga on 28 May 2002 17:41 PDT

You have not addressed my question(s) at all.   
The Baltimore longitudinal study does not explain how inflammation is
involved in Alzheimer's.  The work by de Strooper doesn't answer any
of my questions, and in fact has nothing to do with inflammation since
all his group was measuring was the production of a particular form of
amyloid protein which is not even the form that initiates inflammatory
activity in the brain.
You have not answered my question as to which drugs may work, and your
suggestion that so-called NSAIDs cause bleeding into the liver is not
supported by the literature.
Your answer is completely inadequate.  

The answer by our friend 'jaq-ga' was off topic, trivial, and
misleading.  This researcher does not appear to be qualified at all in
the subject area.

off topic, trivial answer, incorrect statements.  how bad can you get.

While it's not a proven fact as such, inflammation of in the brain is
thought to be a contributing factor (cause) in Alzheimer's Disease,
primarily because amyloid-beta (protein) is an inflammatory protein.

With this in mind, it's reasonable to expect that anti-inflammatory
drugs might slow the progression of the disease, and there have been
studies that do support this. Ibuprofen, naproxen, refcoxib and
aspirin are examples of NSAIDS that could be helpful in preventing or
slowing the disease.

The Alzheimer's Disease Fact Sheet from the Alzheimers Organization
states:
"Scientists are testing two different types of nonsteroidal
anti-inflammatory drugs (NSAIDs) to find out if they slow the disease.
There is evidence that inflammation in the brain may contribute to AD
damage. Scientists believe that anti-inflammatory drugs such as NSAIDs
might help slow the progression of AD. Rofecoxib (Vioxx) and naproxen
(Aleve) are two NSAIDs currently being studied."
http://www.alzheimers.org/pubs/adfact.html

And from "A Guide to Frequently Used Terms" from the same
organization:
Compounds, such as ibuprofen and aspirin, that help fight swelling and
pain. Researchers are investigating NSAIDs as a potential treatment
for Alzheimer's disease because some studies have shown that
inflammatory processes may play a role in the development of this
devastating disease.
http://www.alzheimers.org/trials/clinglos.html#nsaidrugs

New compounds have taken this a step further, though, which "suppress
the cellular signaling processes that trigger inflammation of brain
cells, a hallmark of Alzheimer’s disease..."
( http://www.eurekalert.org/pub_releases/2002-01/nu-ncs012302.php )

If inflammation can be stopped before it starts, the outlook for
Alzheimer's Disease as well as other neurodegenerative diseases looks
very good indeed.

The amyloid protein found post mortem in those with Alzheimer's
Disease is crucially higher than in those without.

From the Neurology Channel:
While some neuritic plaques, or patches, are commonly found in brains
of elderly people, they appear in excessive numbers in the cerebral
cortex of Alzheimer's disease patients. A protein called beta amyloid
occupies the center of these plaques. Surrounding the protein are
fragments of deteriorating neurons, especially those that produce
acetylcholine (ACh), a neurotransmitter essential for processing
memory and learning. (Neurotransmitters are chemicals that transport
information or signals between neurons.)
http://www.neurologychannel.com/alzheimers/


More information here: 

Report on new compounds: 
http://www.eurekalert.org/pub_releases/2002-01/nu-ncs012302.php

Possible ibuprofen solution:
http://www.nature.com/nsu/011108/011108-10.html

Symptoms and statistics: 
http://www.lef.org/protocols/prtcl-006.shtml

Explanation of what happens to the brain: 
http://www.neurologychannel.com/alzheimers/

The best overall web site:
http://www.alzheimers.org/


Search strategy: 
Alzheimer's Disease and NSAIDS
://www.google.com/search?site=swr&hl=en&lr=&q=Alzheimer%27s+disease+amyloid+protein+&as_q=NSAIDS

Alzheimer's Disease and inflammation
://www.google.com/search?site=swr&hl=en&lr=&q=Alzheimer%27s+disease&as_q=inflammation

I hope this helps.

---

Request for Answer Clarification by nish-ga on 12 Jun 2002 10:39 PDT

Wandrer: the question was: How is inflammation involved - cause or  
effect - relationship to amyloid protein - and which anti-inflammatory
drugs and why?
I feel as though I need to repeat the question. Though you put some
effort in you strayed far from my question.
You say: "inflammation of in the brain is thought to be a contributing
factor (cause) in Alzheimer's Disease,primarily because amyloid-beta
(protein) is an inflammatory protein."
 
How does this statement answer my question "how is inflammation
involved"?
If I ask you how your cigar burns and you tell me that burning is
thought to be a contributing factor, does your answer satisfy my
curiosity?
 
Please try again to answer the question, if you want to, but there are
other issues as well.
 
How do you know that "amyloid-beta (protein) is an inflammatory
protein"?
 
You did not address my "cause or effect" question.  To clarify, I am
asking you wether inflammation in the brain CAUSES Alzheimer's
disease, or whether inflammation in the brain is simply an EFFECT of
other processes that cause the disease.
 
Without an answer to my primary question, I can't understand why you
think "it's reasonable to expect that anti-inflammatory drugs might
slow the progression of the disease".
 
Finally, when I ask "which anti-inflammatory drugs and why", it is
insufficient to give me a list of ones being tested.
 
Read &lt;a href=&quot;<a href="http://www.alzforum.org/members/forums/journal/pasinetti/">http://www.alzforum.org/members/forums/journal/pasinetti/</a>&quot;&gt;<a href="http://www.alzforum.org/members/forums/journal/pasinetti/">http://www.alzforum.org/members/forums/journal/pasinetti/</a>&lt;/a&gt; 
, which I found with a simple Google search of &amp;quot;Celebrex Alzheimer&amp;quot;,
and reconsider your glib assumptions about the subject matter of my
question.
 
I hope you can find an answer for me. Remember: my question was posted
here because I could not, after searching on my own, find the answer. 
Can you do better?  

The Researcher did some basic searches and produced lots of links,
etc. using trivial combinations of words in my question, but this is
not the way to research such a question.  With this inadequate method,
the results are obviously inadequate, and extraneous.  The answers
given are alternatively wrong, misleading, or off topic.  This
question requires a Researcher qualified in this subject.

Hello Nish,
You have asked a very tough question to answer right now. In fact
scientists are still discussing whether it is amyloid protein
accumulation or a chronic inflammatory reaction that is the cause of
Alzheimer disease. One review article in the Journal of the American
Medical Association (JAMA, May 8, 2002) seems to imply that amyloid
protein accumulation starts inflammatory reactions and that the
inflammation causes membrane damage to the neurons. When the membranes
are damaged the neurons do not function properly. They also point to
amyloid protein accumulation as important in the oxidative damage and
programmed cell death that is also apparently involved in this very
complex disease process.
http://jama.ama-assn.org/issues/v287n18/rfull/jct10025.html

Other review articles I got from Pub Med appear to disagree with this
JAMA review. There are several articles I got for you. They only have
the abstract of the articles however enough detail is present to give
you a fairly good idea of what they are saying.

This articles states that inflammatory mediators may actually cause
the accumulation of amyloid protein.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11755000&dopt=Abstract

The following article states that interleukin-1 is important in this
process.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11754997&dopt=Abstract

In the case of anti-inflammatory drugs it appears that nonsteroidal
anti-inflammatory drugs (NSAIDS)have been most useful in delaying
onset of full blown Alzheimer disease. Another paper states that
several inflammatory mediators are probably involved and that the use
of COX-1 inhibitors could be of use in treatment of this disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11754986&dopt=Abstract

The following articles points to certain anti-inflammatory drugs that
appear to be of use in delaying onset of full blown Alzheimer disease.
They do mention that steroids were not shown to be useful in treating
this disease.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860350&dopt=Abstract

Hope that this is what you are looking for. I am sorry I can’t give
you THE answer but unfortunately the answer is not yet known.
Nealc-ga

I believe you're looking for answers that are as yet unknown. It's
thought that inflammation is a contributing factor, but whether it is
a base cause is simply not known at this time.

Sorry I can't contribute any more on this subject. Good luck in
finding a satisfactory answer.

How is inflammation involved in Alzheimer's disease?

Example, impaired glucose metabolism increases production of
pro-inflammatory cytokines, like interleukin-1, and
interleukin-6,tumor necrosis factor and certain prostaglandins (PGE2).
 These are then thought to promote conditions that favor plaque and
fibril development.  The proinflammatory factors have a two-pronged
attack 1) damage causing 2)inhibit activity of beneficial factors like
certain growth factors.

Is it cause or effect?  Both, it starts a vicious cycle of
inflammation ->
more inflammatory compounds -> inflammation -> inflammatory compounds.

How does the amyloid protein that is found post mortem relate 
to inflammation?  Amyloid beta is a free-radical generator itself that
then can initiate the proinflammatory cascade.

Which anti-inflammatory drugs might work and why? 

Cyclooxygenase inhibitors (COX) like Aspirin by effecting
cyclooxygenase (involved in prostaglandin production).  Omega 3-fatty
acids compete with arachidonic acid at the COX binding
site-arachidonic acid yields series 2 prostaglandins.

I haven't seen much  on the effectiveness of interleukin or TNF
antagonists,
but I think that prevention is better than cure. Don't overlook the
role of glucose homeostasis in free radical production.

PMID of articles I've read:

[PMID:10753587] 
[PMID:10782042]

Type the PMID in at medline to see abstracts: 



Don't over