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.