Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Clusterin is the newest protein to join all those molecules contributing to the senile plaques of Alzheimer's disease (AD). These sticky insoluble amyloid-beta (Ab) plaques are hallmarks of the disease. Clusterin belongs to a family of proteins that bind Ab and may play one or more cards in neuritic plaque formation. But in vivo proof has been lacking as to clusterin's complicity.

Now a paper in the current Proceedings of the National Academy of Sciences (PNAS), released online July 22, 2002, purports to fill this gap. Its title: "Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease." Its co-authors are largely neurologists and molecular biologists at Washington University in St. Louis.

They bred a mouse model that mimics the signs, symptoms and brain changes of AD to a transgenic animal from which clusterin expression had been knocked out. By 12 months of age, the transgenics had as much Ab accumulation in their brains as the clusterin-plus control mice. However, the clusterin-minus knockouts produced far fewer amyloid fibrils - the raw material of the toxic plaque clumps - and they displayed much less damage to brain cells surrounding the Ab deposits. These results suggest that clusterin makes the Ab more toxic to surrounding neurons. Hence, the co-authors suggest, the protein seems to be an important player in the AD game, and a possible new target for AD therapies.

The paper notes that the probability of amyloid-beta clumping into different insoluble forms in the brain can be influenced by Ab proteins. One example of such a protein is apolipoprotein E4 (apoE4), which is the only proven genetic risk factor for late-onset AD. Whether apolipoproteins other than apoE nudge Ab aggregation and toxicity in vivo is unknown. However, a good candidate player for such effects is apolipoprotein J - also known as clusterin.

In the poker rounds of early onset Alzheimer's disease, the dealer is a lengthy molecule called amyloid precursor protein (APP). The cards it hands around are the genes expressing APP itself and its stubby spin-offs, typically Ab, APOE4 and the mutated peptides presenilin-1 and presenilin-2. The peptides cleaved off from APP, notably soluble amyloid-beta, are 39 to 43 amino acids in length. Conversion of soluble to insoluble plaque-generating amyloid is thought to be a key event in the pathogenesis of AD.

Clusterin is present in AD plaques, up-regulated in the AD brain, associated with soluble Ab in cerebrospinal fluid and can hustle Ab transport across the blood-brain barrier. Still, whether it plays a direct role in AD pathology in vivo has remained unclear. The Science paper concludes that "these findings suggest a role for clusterin in influencing amyloid deposition and the associated neuritic toxicity in vivo."

Chemical/Biochemical Components Used To Create Poliovirus Genome From Git-Go

It may seem odd, but molecular geneticists and microbiologists at the State University of New York at Stony Brook have synthesized the full-length poliovirus complementary DNA sequence. Meanwhile, the World Health Organization is striving to render poliomyelitis clinically extinct, along the lines of successfully wiping out smallpox in the 1980s. The SUNY co-authors emphasize that the world's population is better protected against polio - infantile paralysis - than ever before, thanks to the WHO vaccine effort.

They report their new virus recreation in Science express dated July 11, 2002, under the title: "Chemical synthesis of poliovirus cDNA: Generation of infectious virus in the absence of natural template."

The co-authors used only a genome sequence for guidance to construct a poliovirus that seems identical to its natural counterparts. While this is the first time a genome has been reconstructed without a natural template or blueprint from a living organism, the components they used to recreate the virus' chemical sequence, genetic map and 3-dimensional structure were determined two decades ago.

When poliovirus invades a cell, its replicase - an enzyme that replicates viral genomes - normally starts making complementary strands of the original single-stranded genome. The Science co-authors set to work in the opposite direction, first assembling the basic nucleotide building blocks into complementary DNA versions of the two viral strands. They then generated the virus in a test tube, using another enzyme to transcribe the cDNA into viral RNA. Several neurovirulence experiments in mice confirmed that their synthetic virus had the same infectious properties as the native poliovirus.

"The potential for viral synthesis," their paper concludes, "is an additional important factor for consideration in designing the closing strategies of the poliovirus eradication campaign."

Push-Me, Pull-You Circuit Between Occult HIV Factor And Opposed Gene Hints At Therapies

Besides its immune deficiency attacks, HIV harbors hidden arrows in its quivers. These mysterious molecules counteract host-mediated mechanisms that confer resistance to infection. One HIV arrow is the Vif (virion infectivity factor) protein, which is encoded by human and simian AIDS viruses. HIV-1 Vif seems to be required during the late stages of virus replication. There, Vif suppresses an innate antiviral factor that resides in human T cells - the prime targets of HIV - and therefore is rarely perceptible. If Vif is lacking, this anti-Vif factor makes progeny viral particles non-infectious.

Microbiologists at the University of Pennsylvania in Philadelphia flesh out this dual dance in Nature dated July 14, 2002. Their paper is titled: "Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein." Their unique cellular gene, which the co-authors have dubbed CEM15, is none other than that antiviral factor. The pro-infection presence of Vif overcomes its antiviral action. "Because the Vif:CEM15 regulatory circuit is critical for HIV-1 replication," the paper concludes, "perturbing the circuit may be a promising target for future HIV/AIDS therapies."

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