. Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol. 2005 Nov;7(11):1118-23. PubMed.

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  1. Researchers have long speculated that the Aβ peptide might have a physiological function. Unfortunately, evidence of a normal role for Aβ in cellular processes has been notoriously difficult to obtain and has led to the prevailing notion that Aβ is merely a toxic byproduct of APP metabolism—nasty “junk,” if you will. Strong evidence for a physiological function of Aβ did not emerge until 2003, when work by Malinow and colleagues suggested that Aβ may act as a negative regulator of excitatory synaptic transmission (Kamenetz et al., 2003). Surprisingly little else has been published about this putative function of Aβ, for reasons that are unclear. Now, the paper by Hartmann and colleagues reports an exciting new role for Aβ in regulating both cholesterol and sphingomyelin biosynthesis, apparently via two complex feedback loops that center on γ-secretase. The evidence they present in favor of this complex feedback regulation is extensive and quite compelling. Adding a Baroque yet intriguing twist, they discovered that the C-terminus of Aβ determines which of the two lipid pathways is to be regulated. Aβ40 inhibits HMG CoA reductase and thus lowers cholesterol levels, while Aβ42 directly activates SMase and therefore lowers sphingomyelin levels. Moreover, Aβ42-raising FAD mutations in presenilin cause cholesterol levels to increase (because reduced Aβ40 levels relieve HMG CoA reductase inhibition) and sphingomyelin levels to fall (due to Aβ42-induced stimulation of SMase). In pathology, this feedback loop could lead to a vicious circle of ever-increasing Aβ42 and cholesterol levels, and could provide a plausible explanation for the observed relationships between cholesterol levels, Aβ generation, and AD. Thus, the results of Hartmann and colleagues suggest that the variable C-termini of Aβ are not just mistakes of an indiscriminate γ-secretase, but that the Aβ40/Aβ42 ratio may in fact be physiologically determined for the regulation of lipid homeostasis. This is a fascinating paper that has far-reaching implications for the entire field.

    References:

    . APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.

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