Letters

Prions: A Piece of the Puzzle?

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Science  07 Sep 2012:
Vol. 337, Issue 6099, pp. 1172
DOI: 10.1126/science.337.6099.1172-a
CREDIT: MEHMET ALI CIDA/ISTOCKPHOTO.COM

In his Perspective “A unifying role for prions in neurodegenerative diseases” (22 June, p. 1511), S. B. Prusiner proposes that Alzheimer's disease (AD) is a prion disorder (1). News publications have speculated that AD may be transmitted by blood transfusion (2), and caution has been thrown to the wind in Internet outlets. Prusiner's model comes from experiments in which Aβ peptide (the immediate precursor of AD amyloid plaques) induced aggregation in transgenic mice or primates after injection of AD brain extracts (3, 4) or purified and synthetic Aβ peptides (4, 5). However, no plaque appeared in monkeys injected with synthetic Aβ, raising questions about the direct translation of animal results to humans.

This technical critique ignores fundamental questions of AD etiology. Extracellular Aβ accumulation always accompanies the disease, but is it a cause or a result? How can we explain memory deficits that familial AD model mice exhibit before evidence of plaque deposition (6)? Given that direct neuron-to-neuron transmission of nonfibril Aβ exists (7), could AD pathogenesis depend on intracellular, nonplaque Aβ?

Multiple environmental risks for AD have been identified; where would they fit into a prion model? In addition to dietary cholesterol, factors such as mid-life exercise, nutrition, education, and early-life exposure to environmental hazards may modify amylodogenesis and AD (8). Late-onset neurodegenerative disorders, such as AD, can be explained by the latent early-life associated regulation (LEARn) pathway, in which environmental factors act epigenetically, long before the onset (8).

Other evidence suggests that AD has some genetic basis, in seeming contradiction to a prion model. For example, apolipoprotein E is a genetic risk factor. Genetic evidence for the role of the Aβ precursor protein (APP) in age-related cognitive decline and AD suggests that APP protective mutation carriers have lower Aβ peptide levels for their entire lives (9).

There is no denying that Aβ subunits play a role in nucleation of Aβ aggregates, but to call them prions, in the sense of the naturally infectious particles that catalyze disease based entirely on their own refolding and aggregation, ignores a great deal of evidence in the field and stirs up public fear prematurely.

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