Editors' ChoiceNeuroscience

Cholesterol and Alzheimer’s disease

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Science Signaling  02 Apr 2019:
Vol. 12, Issue 575, eaax4932
DOI: 10.1126/scisignal.aax4932

Inhibiting the accumulation of cholesterol in iPSC-derived neurons prevents the accumulation of both β-amyloid and tau.

Alzheimer’s disease (AD) is characterized by the formation of β-amyloid (Aβ) plaques in the brain and intracellular aggregation of tau in neurons. Therapies for preventing or clearing Aβ plaques have not shown success in clinical trials, suggesting that both Aβ and tau aggregations may need to be targeted to treat AD. Van der Kant et al. found that statins, inhibitors of both cholesterol and isoprenoid biosynthesis, reduced the accumulation of tau in induced pluripotent stem cells (iPSCs) derived from a familial AD (FAD) patient with a duplication of APP, which encodes the amyloid precursor protein that is cleaved to generate Aβ. Inhibiting isoprenoid biosynthesis did not reduce tau accumulation, but various pharmacological approaches for reducing cholesterol biosynthesis or accumulation did. The depletion of cholesterol esters, the form in which cholesterol is stored in cells, rather than the depletion of free cholesterol, reduced tau accumulation. Statins reduced Aβ accumulation in the culture medium of both APP-duplicated and APP-null iPSC-derived neurons. Mutating the cholesterol-binding domain of APP prevented statins from reducing Aβ secretion but did not prevent them from reducing tau, indicating that the ability of statins to reduce tau accumulation did not depend upon APP or Aβ. CYP46A1 is a neuron-specific cytochrome P450 enzyme that converts cholesterol to 25-hydroxycholesterol, which can be secreted, cross the blood-brain barrier, and become degraded in the liver. Efavirenz, an FDA-approved pharmacological inhibitor of CYP6A1, stimulated 25-hydroxycholesterol secretion and reduced tau accumulation in both APP-duplicated and APP-null neurons and was less toxic to iPSC-derived astrocytes than were statins. These findings may explain conflicting reports regarding the effects of statins on the development and progression of AD (see commentary by Blanchard and Tsai) and suggest that targeting CYP46A1 should be further explored as a possible AD intervention.

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