Cholesterol defect is marked across multiple rodent models of Huntington's disease and is manifest in astrocytes.
Brain cholesterol, which is synthesized locally, is a major component of myelin and cell membranes and participates in neuronal functions, such as membrane trafficking, signal transduction, neurotransmitter release, and synaptogenesis. Here we show that brain cholesterol biosynthesis is reduced in multiple transgenic and knock-in Huntington's disease (HD) rodent models, arguably dependent on deficits in mutant astrocytes. Mice carrying a progressively increased number of CAG repeats show a more evident reduction in cholesterol biosynthesis. In postnatal life, the cholesterol-dependent activities of neurons mainly rely on the transport of cholesterol from astrocytes on ApoE-containing particles. Our data show that mRNA levels of cholesterol biosynthesis and efflux genes are severely reduced in primary HD astrocytes, along with impaired cellular production and secretion of ApoE. Consistently, in CSF of HD mice, ApoE is mostly associated with smaller lipoproteins, indicating reduced cholesterol transport on ApoE-containing lipoproteins circulating in the HD brain. These findings indicate that cholesterol defect is robustly marked in HD animals, implying that strategies aimed at selectively modulating brain cholesterol metabolism might be of therapeutic significance.
Valenza
Marta
M
Department of Pharmacological Sciences and Centre for Stem Cell Research, Università degli Studi di Milano, 20133 Milan, Italy.
Leoni
Valerio
V
Karasinska
Joanna M
JM
Petricca
Lara
L
Fan
Jianjia
J
Carroll
Jeffrey
J
Pouladi
Mahmoud A
MA
Fossale
Elisa
E
Nguyen
Huu Phuc
HP
Riess
Olaf
O
MacDonald
Marcy
M
Wellington
Cheryl
C
DiDonato
Stefano
S
Hayden
Michael
M
Cattaneo
Elena
E
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013261:Sterols / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D001057:Apolipoproteins E; D004676:Myelin Basic Protein; D013261:Sterols; D050825:Synaptosomal-Associated Protein 25; D002784:Cholesterol