ALZHEIMER’S DISEASE: FIRST STEPS TOWARD A CURE
In the six years since “2000 World Alzheimer’s Congress” the subject matter of the neurological catastrophe which overwhelms so many of us in our later years has undergone explosive development. The subject itself has fragmented in various sub-disciplines, which have provided new understandings in a number of related and unrelated fields, showing how unified neurobiology is becoming. However, it seems we are not closer to finding a cure. It is mainly because aetiology remains unclear and the disease may have more than one cause; indeed many researchers think the name may cover a variety of subtly different conditions. Nevertheless, significant progress in understanding pathogenesis at molecular level, has permitted the development of new drugs and other agents, now on trials, which could prove some effectiveness in preventing and treat the disease (Michael S. Wolfe, Shutting Down Alzheimer’s. Sci. Am. 294 (5): 60-67, 2006; by the same author: Therapeutic Strategies for Alzheimer’s Disease. Nature Reviews Drug Discovery 1, 859-866, 2002; more information at www.alzforum.org and www.alz.org).
The two key features of the Alzheimer’s dementia are plaques and tangles. Amyloid plaques, made by degenerating axons and dendrites around a core consisting of beta-amyloid protein, are frequently targeted by microglia. Neurofibrillary tangles consist of twisted neurofilaments made by fosforilated tau protein. There has been a long lasting controversy over which comes first, β-Amyloid plaques (BAP) outside cells, or tau neurofibrillary tangles (NFTs) inside nerve cells bodies and processes. Alzheimer researchers are thus often divided into BAP-tists and Tau-ists.
Now, as the amyloid-cascade is considered more than a simple hypothesis, the process triggered by a 42-43 aminoacids peptide (Aβ) first isolated by Glenner & Wong and able to assemble into fiberlike structures as demonstrate by Lansbury, has been linked to tangles located inside neurons. Aggregates of Aβ outside a neuron can initiate a cascade of events that include the alteration of tau inside the cell. This connection further support the idea to develop drugs targeting β-secretase and γ-secretase, two key enzymes in Aβ synthesis.
β-secretase falls into aspartyl protease family, a subset of proteases including the enzyme involved in replicating HIV. β-secretase, as well as other aspartyl proteases, employ a pair of aspartic acids and water to cut APP. β-secretase inhibitors are not yet ready for clinical trials. Many tested molecules was non small enough to effectively penetrate Blood-Brain Barrier (BBB).
The γ-secretase enzyme is a founding member of a new class of proteases that apparently wield water within cellular membranes to cut their target molecule. The inhibitors of γ-secretase easily penetrate BBB, but they interfere with other critical molecular processes, such as Notch signalling. In normal conditions, γ-secretase acts by cutting the cell-surface Notch protein, which sends signals about cell fate and maturation to the nucleus, through its intracellular active fragment. Although γ-secretase inhibitors can cause severe toxic effects in mice, pharmaceutical brand Eli Lilly has developed such a molecule as drug candidate, now under evaluation in patients with early Alzheimer’s (phase II clinical trials), as it passed safety tests in volunteers (phase I clinical trials).
Active immunization is no more considered as a promising perspective since patients in phase II developed encephalitis forcing a stop to trials in 2002. A passive immunization treatment developed by Elan Corporation has recently reached phase II clinical trials.
An interesting non-immunological strategy underlies the employ of Alzhemed, a small molecule developed by Neurochem, which prevents heparin binding to Aβ. Because heparin makes the peptide more likely to form deposits, Alzhemed bindings to the same sites of this polysaccharide on Aβ reduces amyloid plaques formation.
Cholesterol-lowering drugs called statins (such as Pfizer’s Lipitor) are under trials (Phase III) to establish a real efficacy.
The cell-based therapy developed by Mark Tuszynki and his colleagues at University of California in San Diego is a strategy for delivering NGF, a large protein that could not otherwise penetrate the brain. The study included only a few subjects and lacked of a proper control, however it has showed a so relevant reduction of cognitive decline in patients to warrant further clinical trials.