PHILADELPHIA—Although amyloid plaques and neurofibrillary tangles continue to be a focus of therapeutic interest in molecular pathology studies of Alzheimer’s disease, in recent years attention has turned to disease processes that are generated before the deposition of amyloid filaments outside the neurons. Even if plaques and tangles could be successfully eradicated in the brains of Alzheimer’s patients, the thinking goes, curing Alzheimer’s disease would still require these other processes to be therapeutically targeted.

What is emerging is a theoretical approach to Alzheimer’s disease and other neurodegenerative disorders that links the onset and progression of brain degeneration mechanistically to abnormal interactions between brain proteins. These disease proteins assemble into filaments, and the filaments in turn form aggregates within or around brain cells. Multiple disease pathways then converge to cause protein misfolding and the formation of toxic amyloid deposits composed of tau in tangles, β-amyloid in plaques, and α-synuclein in Lewy bodies.

More and more, Alzheimer’s disease is being regarded as a disconnection syndrome, and the cause of this dysfunction appears to be axonal transport failure, said John Q. Trojanowski, MD, PhD, Codirector of the Center for Neurodegenerative Disease Research at the University of Pennsylvania in Philadelphia. At the Ninth International Conference on Alzheimer’s Disease and Related Disorders, Dr. Trojanowski reported the results of a study in which either a low or medium dose of the microtubule-stabilizing drug paclitaxel given to transgenic mice resulted in an improvement in axonal transport, an increase in microtubules, and an amelioration of motor impairment in genetically engineered mice that overexpress human tau proteins to generate animal models of the tau pathologies found in the brains of patients with neurodegenerative disease. “We were able to restore the numbers of microtubules and also the weakness phenotype, the motor weakness that these mice had,” he said. “Behaviorally they improved, their axonal transport was improved, microtubules increased —without having to eliminate the tau aggregates and inclusions.”

The clinical and public health implications of such a finding are potentially enormous, in Dr. Trojanowski’s view. He cited work by Claudia H. Kawas, MD, suggesting that attenuation of the disease by as little as five years could have a significant impact on prevalence, incidence, and cost. “We may not need to eliminate tangles to cure Alzheimer’s disease,” Dr. Trojanowski posited. “Remember what Claudia Kawas has shown in the modeling scheme she devised … that a five-year delay in the onset of Alzheimer’s disease reduces the prevalence and incidence by half, as well as the cost to society.”

ALZHEIMER’S “DISEASES”?

Dr. Trojanowski emphasized that knowing about the processes leading to a “broken brain” in Alzheimer’s disease can also serve as a road map for learning how to “fix” the brain with Alzheimer’s disease. Among neurodegenerative diseases, the most common ones—and even some of the less common ones—are brain amyloidoses, he said. Together, they constitute an entire class of protein-misfolding diseases, characterized by proteins that assemble into filaments with specific physical properties. The filaments are virtually indistinguishable between one disease and another, but the building block proteins of lesions such as senile plaques, tangles, or Lewy bodies are distinctly different at the amino acid sequence level.

Common to all of these diseases is the fact that the disease protein has normal functions, according to Dr. Trojanowski. “It wasn’t created by a malignant god or deity who wanted to punish humanity with disease proteins that would run amok in their brain. The proteins have functions,” he said. “One can exploit insights into the normal functions of these proteins for therapeutic benefit. Let me just emphasize that Alzheimer’s disease refers to a dementia characterized by distinct clinical and neuropathologic features that are assumed to represent a single neurodegenerative disorder, I don’t think it’s a single entity.”

There are multiple causes of Alzheimer’s disease, both genetic and sporadic forms—as is true of other neurodegenerative diseases characterized by brain amyloidosis, Dr. Trojanowski explained. Because Alzheimer’s disease is the most common neurodegenerative disease, it also is the most common tauopathy, he elaborated. It is also the most common form of synucleinopathy, since 50% of sporadic and familial Alzheimer’s disease patients have Lewy bodies.

“Having said that, of course, we make the diagnosis of Alzheimer’s disease based on autopsy examination of the brain,” he noted. “It’s a dementing condition that is diagnosed by the recognition of plaques and tangles postmortem.”

GIVING LEGS TO A FAST AXONAL TRANSPORT THEORY

Since the early 1990s Dr. Trojanowski and his colleagues at the University of Pennsylvania and other institutions have reported a series of preclinical study results that, taken together, constitute a new therapeutic approach to Alzheimer’s disease. Rather than depend on the elimination of aggregates and inclusions, this approach compensates for the loss of normal functions that accrues when the disease protein tau is sequestered in the aggregate. “Targeting losses of tau function for Alzheimer’s disease drug discovery, I think, has legs,” Dr. Trojanowski remarked.

In the latest study reported by his group, the dose-dependent improvements of fast axonal transport and motor behavior in the transgenic mice treated with paclitaxel support the investigators’ working hypothesis that microtubule stabilization may be a useful therapeutic strategy for Alzheimer’s disease and other tauopathies. Intracellular accumulations of filamentous tau inclusions are characteristic of Alzheimer’s disease and rarer tauopathies such as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Earlier studies by Dr. Trojanowski’s group demonstrated that transgenic mice engineered to overexpress the shortest human tau isoforms in neurons of the nervous system acquired an age-dependent neurodegenerative disease marked by such features as a reduced number of microtubules, impaired axonal transport, and motor weakness. In addition, other studies provided experimental evidence that tau gene mutations in FTDP-17 may be pathogenic by altering the ratio of microtubule-binding repeat tau isoforms.

To test their hypothesis about the usefulness of microtubule-stabilizing drugs in offsetting the loss of normal tau function, the investigators injected the transgenic mice intraperitoneally with a low, medium, or high dose of paclitaxel once a week for 12 weeks. Axonal transport analyses showed that mice receiving the low or medium dose of paclitaxel had an increase in the rate and amount of newly synthesized ³⁵S-methionine–labeled proteins traveling in the fast axonal transport component in spinal ventral root axons, compared with controls. The treated mice also showed a comparative increase in the number of microtubules observed in the ventral root axons, as well as improvement of motor function.

“We’re very encouraged by this work,” Dr. Trojanowski said. “We think this is proof of the concept that correcting a loss-of-function defect for a disease protein is a viable therapeutic strategy for neurodegenerative diseases.”

FROM ANIMAL MODELS TO THE BEDSIDE

The challenge now is for investigators to move from successful animal models to viable clinical strategies, Dr. Trojanowski said. As he explained, each of the steps in the molecular pathology of Alzheimer’s disease is now a target of therapy, and there are several avenues of therapeutic intervention being explored. “This is something that all of us who speak to patients and their families tell them,” he said, “that we have moved a considerable distance from even a mere five or 10 years ago to the point where insights into how the brain is broken in Alzheimer’s disease is giving rise to many ideas about how to fix it.”

NR

—Fred Balzac

Suggested Reading
Higuchi M, Lee VM, Trojanowski JQ. Tau and axonopathy in neurodegenerative disorders. Neuromolecular Med. 2002;2:131-150.
Kawas CH, Brookmeyer R. Aging and the public health effects of dementia. N Engl J Med. 2001;344:1160-1161.
Zhang B, Higuchi M, Yoshiyama Y, et al. Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci. 2004;24:4657-4667.

Return to table of contents