RESEARCH ARTICLE: Alzheimer optimists face reality check

[Guest guest]

http://news.bmn.com/sreport/previous?day=021025 & story=1

Alzheimer optimists face reality check

24 October 2002

by Apoorva Mandavilli

The mood among Alzheimer's disease researchers last year was euphoric.

Scientists were " most definitely, unquestionably " close to some real

solutions, Hardy, then director of the Center for Neuroscience at the

Mayo Clinic in Florida, had claimed at the time. A year later, however, the

tone is decidedly more somber.

A colleague of Hardy's, Hutton, associate professor of neuroscience

at the Mayo Clinic, was equally optimistic a year ago, but now admits that

optimism was premature.

" There's a recognition that clinical trials and therapies aren't going to

happen overnight, " said Hutton. " It's going to be a longer process than we

perhaps anticipated. "

This time last year, drug company Elan was poised to begin Phase II trials

of a much-publicized vaccine against the disease, while other companies

touted promising inhibitors of enzymes critical in disease progression. The

amyloid cascade hypothesis, which holds that deposition of amyloid-beta is

the central event in the disease, seemed all but proven.

But in January, Elan, along with partner Wyeth-Ayerst Laboratories,

suspended its trial after 15 participants developed central nervous system

inflammation and an acute worsening of Alzheimer's symptoms. Although

researchers have not abandoned the vaccine approach, there is much more

discussion about precautions and procedures, and much less talk of a

definitive cure.

" Everyone was disappointed that the vaccine was making people sick, " said

Hutton. Although the development is " not a huge setback, " he added, " what

we've seen over the last year is a more realistic attitude to the way

therapy is going to work. "

Among inhibitors to beta- and gamma-secretases, several of which were close

to clinical trials last year, no single compound has emerged as leader. The

amyloid debate - whether amyloid is a cause or by-product of the disease -

is no closer to resolution, nor are other contentious questions in the

field.

One prominent discussion has centered on the identity of gamma-secretase,

which catalyzes the last step in amyloid-beta production. Based on solid

biochemical and pharmacological evidence, many researchers have pointed to

the protein presenilin, mutations in which are linked to familial

Alzheimer's disease, as the elusive gamma-secretase.

In recent months, however, several different groups have identified at least

three other proteins required for gamma-secretase activity. Inhibiting any

of the four proteins - presenilin 1, nicastrin, pen-2, and aph-1 -

eliminates enzyme action, researchers have found.

That immediately makes experiments much more complicated, says Gopal

Thinakaran, assistant professor of neurobiology at the University of

Chicago. For any cell biological experiment, scientists now have to

introduce five proteins, including the amyloid precurosr protein (APP).

" It's not an easy task, " Thinakaran said. " The game is getting a little

harder to play. "

In a forthcoming issue of Neurobiology of Disease, Thinakaran and his

colleagues further complicate the picture. Presenilin is not limited to

catalytic activity and may fulfil multiple roles in different parts of the

cell, they suggest.

Earlier experiments have shown that presenilin mutants (which lack both

presenilin 1 and 2, encoded by the genes PS1 and PS2) fail to form the

catalytic complex properly and show decreased gamma-secretase activity,

although activity is not abolished.

Gamma-secretase normally cleaves the C-terminal fragment of APP, and the

full-length peptide is not a substrate, notes Thinakaran. But, remarkably,

he says, the PS1-PS2 double mutant affects maturation and trafficking of the

full-length peptide.

" That tells us that presenilin is doing something to the full-length

peptide, before it is cleaved by alpha- and beta-secretase, " he said.

In the mutant, APP is hyper-glycosylated and greater numbers of the peptide

leave the endoplasmic reticulum for the cell surface, suggesting that

presenilin influences APP folding and maturation. " Presenilin clearly plays

a co-chaperone type of role, " Thinakaran said.

The researchers have not ruled out an enzymatic role for presenilin,

however. " People always thought there was something they could not account

for in terms of presenilin and APP, " said Thinakaran. " It clearly plays

multiple roles in the biology of APP. "

The results " don't surprise me in the least, " said Hutton. Whatever role

presenilin may play, it's clear that gamma-secretase acts on substrates

other than APP, he says, and one of those substrates may very well affect

APP trafficking.

As scientists unravel such complex mechanisms in Alzheimer's disease, common

threads have begun to emerge between AD and other neurodegenerative

disorders including Parkinson's disease, Huntington's and amyotrophic

lateral sclerosis (ALS).

For example, the E4 allele of apolipoprotein E (ApoE) is famously associated

with the risk of Alzheimer's disease, with the severity of multiple

sclerosis, and the age of onset of ALS.

In the largest study yet of ApoE and Parkinson's disease, neurologist

Vance now reports significant associations between the E4 haplotype

and disease occurrence in families with at least two affected members.

Vance, who collaborated with researchers at GlaxoKline, presented the

results earlier this month at the American Society of Human Genetics (ASHG)

meeting in Baltimore.

But what's the link between lipoproteins and nerve damage? " There's no hint

of a mechanism, " said Vance. " That's the Nobel Prize here. " But as the list

of implicated diseases grows, " we as scientists ought to be able to

intersect those problems, and come up with a mechanism, " he said.

One common pattern in neurodegenerative disorders is the presence of protein

aggregates, such as amyloid plaques and Lewy bodies, which may be either a

cause or by-product of the disease process.

The Lewy bodies in the brains of patients with Parkinson's disease contain

alpha-synuclein, a protein of unknown function. Two known mutations in the

protein are linked to familial forms of the disease. Now, neurologist

Han-Xiang Deng, associate research professor of neurology at the University

of Chicago, and his colleagues have created a transgenic mouse that they

claim is the best mouse model for Parkinson's.

In the model, details of which are unpublished, mice express a

dominant-negative mutant form of alpha-synuclein and develop

Parkinson's-like symptoms, says Deng. At 300 days old, the mice have a

full-blown neurological disorder characterized by bradykinesia, posture and

gait problems.

Unlike other mouse models, Deng says, the mice also lost nearly half of all

dopaminergic neurons. " This is the only [model] that shows typical phenotype

and pathology, " he said.

Interestingly, Deng's mice, and some other models of Parkinson's disease, do

not have Lewy bodies, Deng notes. Based on those observations, " it's clear

that Lewy body is not required for the disease, " he said.

Although the mice do not have Lewy bodies, the model is an accurate

reflection of the disease and is ideal for testing drugs such as p53

inhibitors, Deng adds. Using a different mouse model, researchers at the US

National Institutes of Health are now reporting success with p53 inhibitors

in preventing nerve damage.

If all goes well, human clinical trials could begin in two to three years,

the NIH researchers say. But they caution that they need to make sure the

inhibitors don't cause severe side effects.

After the suspension of the Elan trial, most researchers in the field are

now more cautious about taking drugs to clinical trials, notes Hutton.

Still, drugs aimed at amyloid-beta, the secretase enzymes, and other targets

will eventually yield effective therapy, he says. " I still believe we're

taking the right approach with all these drugs, " said Hutton. " It's just a

matter of time. "

[Guest guest]

http://news.bmn.com/sreport/previous?day=021025 & story=1

Alzheimer optimists face reality check

24 October 2002

by Apoorva Mandavilli

The mood among Alzheimer's disease researchers last year was euphoric.

Scientists were " most definitely, unquestionably " close to some real

solutions, Hardy, then director of the Center for Neuroscience at the

Mayo Clinic in Florida, had claimed at the time. A year later, however, the

tone is decidedly more somber.

A colleague of Hardy's, Hutton, associate professor of neuroscience

at the Mayo Clinic, was equally optimistic a year ago, but now admits that

optimism was premature.

" There's a recognition that clinical trials and therapies aren't going to

happen overnight, " said Hutton. " It's going to be a longer process than we

perhaps anticipated. "

This time last year, drug company Elan was poised to begin Phase II trials

of a much-publicized vaccine against the disease, while other companies

touted promising inhibitors of enzymes critical in disease progression. The

amyloid cascade hypothesis, which holds that deposition of amyloid-beta is

the central event in the disease, seemed all but proven.

But in January, Elan, along with partner Wyeth-Ayerst Laboratories,

suspended its trial after 15 participants developed central nervous system

inflammation and an acute worsening of Alzheimer's symptoms. Although

researchers have not abandoned the vaccine approach, there is much more

discussion about precautions and procedures, and much less talk of a

definitive cure.

" Everyone was disappointed that the vaccine was making people sick, " said

Hutton. Although the development is " not a huge setback, " he added, " what

we've seen over the last year is a more realistic attitude to the way

therapy is going to work. "

Among inhibitors to beta- and gamma-secretases, several of which were close

to clinical trials last year, no single compound has emerged as leader. The

amyloid debate - whether amyloid is a cause or by-product of the disease -

is no closer to resolution, nor are other contentious questions in the

field.

One prominent discussion has centered on the identity of gamma-secretase,

which catalyzes the last step in amyloid-beta production. Based on solid

biochemical and pharmacological evidence, many researchers have pointed to

the protein presenilin, mutations in which are linked to familial

Alzheimer's disease, as the elusive gamma-secretase.

In recent months, however, several different groups have identified at least

three other proteins required for gamma-secretase activity. Inhibiting any

of the four proteins - presenilin 1, nicastrin, pen-2, and aph-1 -

eliminates enzyme action, researchers have found.

That immediately makes experiments much more complicated, says Gopal

Thinakaran, assistant professor of neurobiology at the University of

Chicago. For any cell biological experiment, scientists now have to

introduce five proteins, including the amyloid precurosr protein (APP).

" It's not an easy task, " Thinakaran said. " The game is getting a little

harder to play. "

In a forthcoming issue of Neurobiology of Disease, Thinakaran and his

colleagues further complicate the picture. Presenilin is not limited to

catalytic activity and may fulfil multiple roles in different parts of the

cell, they suggest.

Earlier experiments have shown that presenilin mutants (which lack both

presenilin 1 and 2, encoded by the genes PS1 and PS2) fail to form the

catalytic complex properly and show decreased gamma-secretase activity,

although activity is not abolished.

Gamma-secretase normally cleaves the C-terminal fragment of APP, and the

full-length peptide is not a substrate, notes Thinakaran. But, remarkably,

he says, the PS1-PS2 double mutant affects maturation and trafficking of the

full-length peptide.

" That tells us that presenilin is doing something to the full-length

peptide, before it is cleaved by alpha- and beta-secretase, " he said.

In the mutant, APP is hyper-glycosylated and greater numbers of the peptide

leave the endoplasmic reticulum for the cell surface, suggesting that

presenilin influences APP folding and maturation. " Presenilin clearly plays

a co-chaperone type of role, " Thinakaran said.

The researchers have not ruled out an enzymatic role for presenilin,

however. " People always thought there was something they could not account

for in terms of presenilin and APP, " said Thinakaran. " It clearly plays

multiple roles in the biology of APP. "

The results " don't surprise me in the least, " said Hutton. Whatever role

presenilin may play, it's clear that gamma-secretase acts on substrates

other than APP, he says, and one of those substrates may very well affect

APP trafficking.

As scientists unravel such complex mechanisms in Alzheimer's disease, common

threads have begun to emerge between AD and other neurodegenerative

disorders including Parkinson's disease, Huntington's and amyotrophic

lateral sclerosis (ALS).

For example, the E4 allele of apolipoprotein E (ApoE) is famously associated

with the risk of Alzheimer's disease, with the severity of multiple

sclerosis, and the age of onset of ALS.

In the largest study yet of ApoE and Parkinson's disease, neurologist

Vance now reports significant associations between the E4 haplotype

and disease occurrence in families with at least two affected members.

Vance, who collaborated with researchers at GlaxoKline, presented the

results earlier this month at the American Society of Human Genetics (ASHG)

meeting in Baltimore.

But what's the link between lipoproteins and nerve damage? " There's no hint

of a mechanism, " said Vance. " That's the Nobel Prize here. " But as the list

of implicated diseases grows, " we as scientists ought to be able to

intersect those problems, and come up with a mechanism, " he said.

One common pattern in neurodegenerative disorders is the presence of protein

aggregates, such as amyloid plaques and Lewy bodies, which may be either a

cause or by-product of the disease process.

The Lewy bodies in the brains of patients with Parkinson's disease contain

alpha-synuclein, a protein of unknown function. Two known mutations in the

protein are linked to familial forms of the disease. Now, neurologist

Han-Xiang Deng, associate research professor of neurology at the University

of Chicago, and his colleagues have created a transgenic mouse that they

claim is the best mouse model for Parkinson's.

In the model, details of which are unpublished, mice express a

dominant-negative mutant form of alpha-synuclein and develop

Parkinson's-like symptoms, says Deng. At 300 days old, the mice have a

full-blown neurological disorder characterized by bradykinesia, posture and

gait problems.

Unlike other mouse models, Deng says, the mice also lost nearly half of all

dopaminergic neurons. " This is the only [model] that shows typical phenotype

and pathology, " he said.

Interestingly, Deng's mice, and some other models of Parkinson's disease, do

not have Lewy bodies, Deng notes. Based on those observations, " it's clear

that Lewy body is not required for the disease, " he said.

Although the mice do not have Lewy bodies, the model is an accurate

reflection of the disease and is ideal for testing drugs such as p53

inhibitors, Deng adds. Using a different mouse model, researchers at the US

National Institutes of Health are now reporting success with p53 inhibitors

in preventing nerve damage.

If all goes well, human clinical trials could begin in two to three years,

the NIH researchers say. But they caution that they need to make sure the

inhibitors don't cause severe side effects.

After the suspension of the Elan trial, most researchers in the field are

now more cautious about taking drugs to clinical trials, notes Hutton.

Still, drugs aimed at amyloid-beta, the secretase enzymes, and other targets

will eventually yield effective therapy, he says. " I still believe we're

taking the right approach with all these drugs, " said Hutton. " It's just a

matter of time. "