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The translational potential of cholesterol-based therapies for neurological disease

Nature Reviews Neurology volume 19, pages 583–598 (2023)Cite this article

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Abstract

Cholesterol is an important metabolite and membrane component and is enriched in the brain owing to its role in neuronal maturation and function. In the adult brain, cholesterol is produced locally, predominantly by astrocytes. When cholesterol has been used, recycled and catabolized, the derivatives are excreted across the blood–brain barrier. Abnormalities in any of these steps can lead to neurological dysfunction. Here, we examine how precise interactions between cholesterol production and its use and catabolism in neurons ensures cholesterol homeostasis to support brain function. As an example of a neurological disease associated with cholesterol dyshomeostasis, we summarize evidence from animal models of Huntington disease (HD), which demonstrate a marked reduction in cholesterol biosynthesis with clinically relevant consequences for synaptic activity and cognition. In addition, we examine the relationship between cholesterol loss in the brain and cognitive decline in ageing. We then present emerging therapeutic strategies to restore cholesterol homeostasis, focusing on evidence from HD mouse models.

Key points

  • Cholesterol homeostasis in the brain is essential for healthy neuronal physiology, and dyshomeostasis of the cholesterol pathway has been implicated in neurological diseases and age-related neuropathology.

  • Reduced cholesterol biosynthesis and levels are found in the brain of animal models of neurological diseases, including Huntington’s disease (HD), as well as in aged animals.

  • Strategies that increase cholesterol biosynthesis and/or levels in the brain, including adeno-associated viral delivery of genes involved in cholesterol homeostasis or direct delivery of exogenous cholesterol, restore neuronal physiology, cognitive decline and healthy behaviour in animal models of HD and ageing.

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Fig. 1: Bloch, Kandutsch–Russell and modified Kandutsch–Russell pathways of cholesterol synthesis.
Fig. 2: Cholesterol production and disposal in astrocytes and neurons.
Fig. 3: Different strategies used to counteract cholesterol defects in the brain of HD mouse models.

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  1. Department of Biosciences, University of Milan, Milan, Italy

    Marta Valenza, Giulia Birolini & Elena Cattaneo

  2. Istituto Nazionale di Genetica Molecolare ‘Romeo ed Enrica Invernizzi’, Milan, Italy

    Marta Valenza, Giulia Birolini & Elena Cattaneo

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Valenza, M., Birolini, G. & Cattaneo, E. The translational potential of cholesterol-based therapies for neurological disease. Nat Rev Neurol 19, 583–598 (2023). https://doi.org/10.1038/s41582-023-00864-5

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