In two separate papers, appearing in this and next week's print editions of the Proceedings of the National Academy of Sciences, and now available online, researchers from the Weill Cornell School of Medicine and Rockefeller University reported new findings on the basic mechanisms behind brain blood flow in response to neural activity known as functional hyperemia.
They showed that the clotbusting enzyme and stroke treatment tPA is involved in controlling functional hyperemia; that functional hyperemia is disrupted by free radicals in Alzheimer's disease; and that by either preventing the formation of free radicals or counteracting them with antioxidants, it is possible to reverse the behavioral symptoms of Alzheimer's in a mouse model of the disease.
In terms of its energy use, the brain is extreme in at least two ways, which at first blush seem contradictory. For one, it guzzles more than its fair share of energy, at least in terms of its weight. Weighing in at roughly 2 percent percent of body weight, the brain uses about 20 percent of the body's energy.
It's an especially complex problem because "unlike the heart or the liver, for example, the brain is not a homogenous organ," Costatino Iadecola, who is professor of neurology and neuroscience at Weill Cornell Medical College and the senior author of both papers, told BioWorld Today. Instead, "you have all these different regions doing different things."
And all that energy needs to be delivered on an as-needed basis. The brain has no mechanism for storing energy and releasing it. Instead, what the brain has evolved is an intricate mechanism for delivering oxygen and glucose on demand, known as functional hyperemia, which matches supply and demand on a moment-to-moment basis.
The idea that disturbances in brain blood flow may contribute to the pathologies of Alzheimer's is not new, Iadecola said. But until recently, it was something of a chicken and egg question: Are the neurons dying because the blood flow is choked off, or is the blood flow reduced because the dying neurons are using less energy?
New mouse models that make it possible to look at the earliest stages of Alzheimer's disease suggest the former is the case. "The new mouse models show that even at a time when they are behaviorally normal, they already have disturbed blood flow to the brain," Iadecola explained.
And in a paper titled, "Nox2-derived radicals contribute to neurovascular and behavioral dysfunction in mice overexpressing the amyloid precursor protein," and slated for the Jan. 29, 2008, issue of PNAS, Iadecola and his colleagues showed that part of the disturbance in functional hyperemia is due to the production of free radicals, and that by either preventing the formation of free radicals or counteracting them with antioxidants, it is possible to reverse the behavioral symptoms of Alzheimer's in animals.
The researchers crossed animals with a mutated form of amyloid precursor protein, which leads to high levels of a-beta peptides - themselves the precursors of amyloid plaques - to those lacking one subunit of NADPH oxidase or Nox-2. Nox-2 is the main producer of free radicals in the vascular system.
Previous work had shown that knocking out Nox-2 can counteract the effect of A-beta peptides on blood flow. But those studies were performed on young mice, which do not yet have either amyloid plaque deposits or memory deficits.
In their paper, the researchers first compared older and younger mice and found that older mice had deficits in blood flow after stimulation, and that this deficit was worse in the mice with mutated amyloid precursor protein.
However, the deficit was reversed when the mice also were lacking Nox-2, or when they were treated with antioxidants, suggesting that the blood flow deficits were due to an increase in the levels of free radicals in the brain.
Knocking out Nox2 in the Alzheimer's mice did not change the increased levels of A-beta peptide and amyloid plaques. But it did lead to better performance on a memory task and reduced anxiety.
By targeting free radicals "you can reverse not only the vascular deficits, but also the behavioral symptoms - that's the key," Iadecola stressed.
The paper comes on the heels of another publication that appeared in the Jan. 22, 2008, issue of PNAS with the title, "Key role of tissue plasminogen activator in neurovascular coupling."
In that paper, Iadecola and his team investigated the role of the clotbusting enzyme tissue plasminogen activator, best known to biotech folks as the only FDA-approved ischemic stroke treatment, in functional hyperemia.
The researchers studied functional hyperemia in tPA knockout mice, and found that it was impaired. In tPA knockouts, sensory stimulation leads to less of an increase in brain areas processing the stimulation than in wild-type controls.
The researchers then investigated the mechanism by which tPA influences blood flow to active brain areas, focusing on tPA's interaction with a glutamate receptor type, the NMDA receptor.
When NMDA receptors are activated, they activate the enzyme nitric oxide synthase, which leads to the production of nitric oxide; the nitric oxide in turn relaxes blood vessels, allowing for more blood flow in active brain areas.
tPA was necessary for NMDA to activate nitric oxide synthase, but it did not directly change either the current flowing into neurons through the NMDA receptors or the intracellular calcium that is released as a result.
Instead, it appeared to somehow influence the NMDA receptor-dependent phosphorylation of nitric oxide synthase.
Iadecola said between them, the papers suggested it might be possible to treat Alzheimer's by targeting either specifically vascular NADPH oxidase or tPA.
He also said the work adds to other recent studies that suggested the amyloid plaques are not the optimal target for Alzheimer's drugs; recent work has focused on the A-beta peptide intermediates, and Iadecola's new work adds free radical generators to the list.
"The plaques are not really the ultimate problem," Iadecola added. "They are more like a tombstone."