By David N. Leff
There was positive news this week for neurobiologists and neurologists in the field of Alzheimer's disease (AD) research.
A transgenic mouse model for AD, developed at Athena Neurosciences Inc., in South San Francisco, has turned in a convincing scorecard for paralleling key biochemical features of the disease in humans.
Less comforting is the finding that APOE-4, a gene previously thought to account for up to half the cases of late-onset AD, actually reflects the much smaller population of early-onset cases.
It's reported in the January issue of Neurology under the title: "ApoE-4 and age at onset of Alzheimer's disease," but was announced last Friday, Feb. 14, by the National Institute of Mental Health, which sponsored the research.
The most reliable hallmark of Alzheimer's disease, setting it apart from other forms of senile dementia, is * ironically * the presence in certain AD brain regions of senile neuritic plaques. The irony lies in the fact that only a post-mortem brain biopsy can confirm this differential diagnosis.
Those plaques consist largely of a protein called amyloid, which is deposited as beta-amyloid peptide (Aß). It in turn is the breakdown product of a larger molecule, amyloid precursor protein (APP).
This succession of biochemical events speeds up after an individual genetically prone to late-onset AD passes the age of about 70. In others, fortunately only a 10-percent minority, onset can occur from the 30s and 40s up to the 60s.
Among the latter, a clear-cut subset consists of people born with Down's syndrome, who develop AD in early maturity.
From Amyloid To Plaque To Alzheimer's
What's needed is a manageable animal model that tracks AD by age of onset and development of amyloidosis * pile-up of Aß * in regions of the brain marked by plaque in humans.
Just such a model made its bow yesterday in the Proceedings of the National Academy of Sciences (PNAS), dated Feb.18 in a paper titled: "Amyloid precursor protein processing and Aß42 deposition in a transgenic mouse model of Alzheimer disease."
Among the article's 14 co-authors, all at Athena Neurosciences Inc., is the company's director of neurobiology, Dale Schenk.
"A therapeutic target that we and a number of other groups are pursuing right now," Schenk told BioWorld Today, "is the reduction of beta amyloid production. Our mouse model is exquisitely useful for testing compounds to accomplish that."
The Athena rodent, he explained, "is transgenic for APP, and overproduces Aß as well. And it's designed to have an AD-like mutation, the 717 mutation, in that gene."
The 717 mutation wreaks AD havoc in patients who have it. Mechanistically, it causes overproduction of the 42-amino-acid form of the beta-amyloid peptide. "That," Schenk observed, "is thought to be possibly causative for AD."
He continued: "This mouse produces a lot of APP and Aß. As a result, it gets amyloid deposition in the brain, and remarkably, it gets this in the same places in the brain that we see in human autopsies, mainly the cerebral cortex and hippocampus. But we don't see deposition in the human or the murine thalamic region of the brain."
Does this effect in those rodents parallel the human AD condition?
"As far as we know," Schenk allowed, "it does. But with humans you don't know who's going to get AD, so you can't test for it before they do."
The exception to this uncertain principle, he pointed out, is Down's syndrome, which invariably eventuates in early-onset AD.
"They have an extra copy of chromosome 21 and a dramatic rise in Aß, which is very age-dependent," Schenk said. "So, yes, the mice do parallel that subset of human AD patients."
As described in their PNAS paper, the Athena group put together a large, closely matched cohort of their transgenic mice and allowed them to age. At various times during that aging process, Schenk recounted, they sacrificed a group of the animals and analyzed their brain tissue, looking for total APP, amount of beta-amyloid peptide and the amount of APP that's cleaved to activate the peptide at the breakdown site.
"There's something special about this brain-region specificity," Schenk observed, "because we studied mainly heterozygous transgenics * mice with only one copy of the mutated insert gene. But when we turned to homozygous animals, who got a double dose, they actually made a lot of APP in their thalamus, but didn't get amyloid deposition. So there's something special about the cortex of hippocampus that causes this.
"The other key point in the paper," he continued, "is that the 42-amino-acid form of the peptide, which is now thought to be the bad player, goes up drastically as the amyloid deposition occurs. And the percentage of Aß42 rises dramatically with age."
Mice Indentured To AD Drug Discovery
Now, he and his team are studying "the course of inflammation and neuritic degeneration that occurs over time, and what one can do to alter that. And we're using the mice routinely to test for compounds that reduce beta amyloid production."
These candidate drugs are under production with Athena's research partner, Eli Lilly & Co., of Indianapolis, Ind.
The rationale of the compounds, specific protease inhibitors," Schenk said, "is that they interfere in the processing, the breakdown, of APP to form beta-amyloid peptide." But in the same breath, he added: "A lot of it is not understood yet, quite frankly; it's still an area that needs a lot of work." *