20 Sep 2002

The role of amyloid-β (Aβ) in the etiology of Alzheimer’s disease (AD) is still hotly debated. In animal models of AD, for example, neurological deterioration, such as loss of memory and of long-term potentiation (LTP), precede the deposition of Aβ in interneural plaques. What exactly causes these early effects is uncertain, but in today’s early online edition of PNAS, researchers from Columbia University and the New York University School of Medicine report that Aβ may be involved.

First author Ottavio Vitolo and colleagues, under the direction of Michael Shelanski at Columbia, exposed cultured hippocampal neurons to Aβ. This lead to the dissociation of the regulatory and catalytic subunits of protein kinase A (PKA), rendering the kinase inactive. In mice and Drosophila, PKA, which is activated by cAMP, is known to mediate long-term potentiation via phosphorylation of the transcription factor CREB (Cyclic AMP response element binding factor). Consistent with this, the authors found that stimulating Aβ-treated neurons with the neurotransmitter glutamate compromised CREB phosphorylation.

In parallel experiments the authors showed that Aβ impaired LTP. This effect was reversed by addition of the phosophodiesterase inhibitor rolipram or the adenylate cyclase activator forskolin, both of which would increase cytosolic levels of cAMP. Rolipram also attenuated the effect of Aβ on CREB phosphorylation.

Combined, the data indicate that Aβ can have a significant impact on the PKA/CREB pathway, presumably by reducing cAMP concentrations, and that this probably compromises long-term potentiation. How it does so, however, remains to be answered.—Tom Fagan