March 18, 2005: Alzheimer’s Disease (AD), while it mercilessly deprives the afflicted elderly of their healthy minds and imprisons them in a state of deteriorated mental capacity, has already left a seemingly indelible footprint on the minds of the general public. A senile dementia that often leaves the victim bereft of proper intellectual and memory functions, AD usually strikes at a slow, progressive pace, which varies with each person but is uniformly deadly in its final outcome.

Microscopic examination of autopsied brain tissue from AD victims has consistently revealed the presence of twisted protein fragments clustered in “amyloid plaques” and “neurofibrillary tangles.” Areas of brain tissue subjected to these proteinaceous deposits are functionally deficient and are thus susceptible to neuritic dystrophy ultimatively leading to cell death, whose effect is more noticeable in the reduced sizes of brain regions primarily involved in learning and memory processes.

A common inhabitant of these islets of cell death and protein accumulation is the amyloid b-peptide (Ab), a toxic byproduct that arises from the altered degradation of its parent b-amyloid precursor protein (APP). Studies have shown that its production is regulated by enzymes called b- and g-secretases, which chop the protein up into Ab and start an unhealthy cascade of events that causes the cell to self-destruct. The role of these enzymes in AD has therefore made them prime targets for therapeutic intervention.

A scientific collaboration between Paolo Paganetti of the Neuroscience Research Area at the Novartis Institutes for BioMedical Research in Basel and Maurizio Molinari at the Institute for Research in Biomedicine, based in Bellinzona, Switzerland, has come up with a novel method to regulate Ab production in the cell. In a paper published in the latest issue of The Journal of Cell Biology, the researchers engineered human cells to express intracellularly antibody fragments called intrabodies that bind to a region of APP that is cleaved by b-secretase to start the Ab cascade. These intrabodies either contained or lacked a special sequence that tethered them to the endoplasmic reticulum (ER), where they can easily come into contact with newly synthesized APP. Their studies show that subsequent contact between tether-containing intrabodies and APP within the ER interfered with APP’s cleavage and release from the cell, while intrabodies lacking the tether interfered with APP’s ability to be processed by b-secretase.

For cell biologists, this technique may provide them an innovative avenue from which they can validate new therapeutic targets by means of examining the molecular mechanisms of poorly understood cellular events. Additionally, it may strengthen the case for intrabodies to be used as a powerful therapeutic agent that targets the end product of an enzymatic process rather than the enzyme responsible for its production, which therefore bypasses the potential for side effects that may occur when the enzyme’s involvement in other normal biological processes are also disturbed. But most importantly, this approach may provide a ray of hope for AD patients looking for an effective treatment to release them from the prison of their defective minds.