Reduced brain cholesterol biosynthesis in HD rodent models. Brain lathosterol (A) and cholesterol (B) levels were progressively reduced in 10-month-old YAC46 (n = 4), YAC72 (n = 4), and YAC128 (n = 4) and increased in YAC18 (n = 4) mice compared to wt mice (n = 4). Lathosterol (C) and cholesterol (D) levels were reduced in striatum and cortex of YAC72 (n = 6) compared to wt mice (n = 6). Brain lathosterol (E) and cholesterol (F) levels were reduced in Hdh^Q111/111 (12 months; n = 3) compared to Hdh^Q7/7 (n = 5) and Hdh^Q7/111 (n = 5). All data were normalized above weight tissue. Graphs show mean as percentage above controls ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.

Reduced brain 24OHC levels in HD rodent models. At the corresponding symptomatic stage, R6/2 (13 weeks; n = 3), YAC (10 months; n = 4 per group), Hdh^Q7/111 (12 months; n = 5), and Hdh^Q111/111 mice (12 months; n = 3) and HD rats (21 months; n = 3) showed reduced brain 24OHC levels compared to their controls. All data were normalized above weight tissue. Graph shows mean as percentage above controls ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001.

Decreased sterol content in R6/2 synaptosomes and myelin. A, B, Representative Western blot in myelin and synaptosome fractions against MBP (A) and SNAP25 (B), markers of myelin and synaptosomes, respectively. In whole brain (S1), sterols were reduced in R6/2 compared to wt mice (C, D). In myelin fraction, sterols were similar in all samples at 6 weeks of age (C) but were reduced at 12 weeks of age (D) in R6/2 compared to wt samples. In synaptosome fraction, sterols were reduced already at 6 weeks (C) and then at 12 weeks of age (D) in R6/2 compared to wt samples. Data were normalized on protein content. Graphs show the mean of three experiments (per age) as percentage above respective controls ± SEM. *p < 0.05; **p < 0.01.

Reduced ApoE secretion in HD astrocytes and smaller ApoE-containing lipoproteins in HD CSF. A, Hmgcr, cyp51, and 7dhcr mRNA levels were reduced in primary R6/2 astrocytes with respect to wt astrocytes. Each column represents the mean from six Real-time PCR for each of the three independent cultures of R6/2 and wt astrocytes. B–E, Hmgcr, 7dhcr, abca1, and apoE mRNA levels were reduced in primary YAC128 astrocytes and increased in primary YAC18 compared to wt astrocytes. Each column corresponds to the mean of six real-time PCR performed on each of the nine independent cultures of YAC128/YAC18/wt astrocytes. All data (A–E) were normalized on β-actin. Graphs show mean of fold change above controls ± SEM. F, G, Representative Western blots and densitometry for ApoE in whole-cell lysate (F) and in conditioned medium (G) from primary wt and YAC128 astrocytes showed reduced ApoE levels in YAC128 samples (n = 4) compared to wt samples (n = 4). Cellular α-tubulin was used to normalize variations in total cell number in measurements of secreted ApoE. Coomassie staining of the membranes corresponding to proteins in the medium (4G) was also used as loading control. Graphs show mean ± SEM. H, A representative Western blot for ApoE in non-denaturing conditions shows smaller ApoE-containing-lipoproteins in CSF samples from YAC128 mice (HD; n = 2) compared to wt samples (n = 2), as indicated by arrows. Four of six CSF samples from individual YAC128 mice analyzed showed smaller ApoE-containing-lipoproteins compared to the same number of wt mice. *p < 0.05; **p < 0.01; ***p < 0.001.