. Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nat Chem. 2018 Jun;10(6):673-683. Epub 2018 May 7 PubMed.


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  1. These are very helpful results to better understand how cholesterol may impact formation of toxic oligomers. We know about many links between cholesterol and AD, most of which support a risk-increasing role.

    Cholesterol is extremely abundant in the human brain. So abundant that it dwarfs all other lipid species. Handling this vast amount of a single molecule brings its own problems. This only aggravates with the onset of AD neurodegeneration, when suddenly scores of membrane chunks, rich in cholesterol, become dispensable. Yet brain cholesterol catabolism has its own rules and strict limitations, which don’t apply elsewhere in the human body. What happens if the brain cholesterol level increases? One especially curious finding is that Aβ actually has a cholesterol binding motif, suggesting, among other implications, that Aβ fibrils should interact with cholesterol. Habchi et al. now show that cholesterol can drastically hasten Aβ42 aggregation. Not any aggregation, but quite specifically a primary heterologous Aβ42 nucleation process, that leads to Aβ42 oligomers. They didn’t observe any effect on secondary nucleation, which arguably produces the lion’s share of aggregated Aβ. Another impressive result is that the shape of the Aβ42 fibrils in AFM and EM images appears to very similar, irrespective of whether they were produced in presence or absence of cholesterol. This may indicate that the biological properties of cholesterol catalyzed Aβ42 oligomers may not be that different from the ones produced in absence of cholesterol. This is probably welcome news to anyone who studies Aβ42 toxicity.

    As elegant as is the experimental design and as welcome as is the clarity of the results, one needs to keep in mind that these are synthetic molecules in an artificial setting. Neither the membrane, nor the Aβ peptide composition and concentration match the incredibly more complex situation present in neurons or even more so that of a living brain. Having said this, I can’t resist but be fascinated to see that Habchi’s research points towards cholesterol-mediated aggregation having an impact rather early in AD pathogenesis, which is where observational studies seem to typically put it.

    View all comments by Tobias Hartmann
  2. Cholesterol and amyloid accumulation. The known unknowns of a dangerous liaison.

    These findings by Habchi et al. are most interesting. Although politics should be kept outside of the interpretation of scientific data, in 2002, Donald Rumsfeld, the then U.S. Secretary of State for Defense, said: “There are known knowns. There are things we know that we know. There are known unknowns. That is to say, there are things that we now know we don't know. But there are also unknown unknowns.” Paraphrasing David Logan (Logan, 2009), there are many known knowns in biology; however, the number of known unknowns is always far above and beyond the knowns in most fields. As such, there are a few known knowns about cholesterol and AD, but a lot more of known unknowns. 

    One known known is the observation that, in animals, a hypercholesterolemic diet leads to increased amyloid deposition (Refolo et al., 2000). However, such clear-cut observations in animals are not readily translated to the human brain, where one finds more complex interactions between cholesterol and amyloid (Pappolla et al., 2003). 

    It is also known that midlife hypercholesterolemia is a risk factor for AD, as demonstrated in several epidemiological studies (Pappolla et al., 2003; Kivipelto et al., 2006; Kivipelto and Solomon, 2006; Kivipelto et al., 2002; Notkola et al., 1998). However, the interpretation of the published data is marred by (pseudo)controversy, with some investigators claiming a negative association between cholesterol levels in serum and AD (Mielke et al., 2005; Reitz et al., 2008). This controversy is more apparent than real, since most studies showing a positive correlation between high serum cholesterol and AD have examined cholesterol levels at midlife (cohorts' ages ranged from 40 to 59 years) and then correlated these levels to later development of dementia. In contrast, most negative reports only included participants of advanced ages. Autopsy observations are in sync with the positive epidemiological studies, that is, they show that high levels of serum cholesterol correlate with presence of amyloid deposition in human brain only in the youngest subjects but not in the older subjects (Pappolla et al., 2003). Similar observations confirming this age-related dynamic were more recently reported in 2017, using amyloid PET imaging in human subjects by at least two different groups of investigators (Gottesman et al., 2017; Vemuri et al., 2017). 

    A known unknown, then, revolves around the age-related factor (or factors) that acts in concert with cholesterol to drive up Alzheimer’s risk. Important observations by Suzana Petanceska (Petanceska et al., 2003), some time ago, showed that as cholesterol levels increase, so does the level of ApoE expression in the brain. However, we do not know whether such a phenomenon could be age-related. Since ApoE is a carrier of both, cholesterol and Aβ, the observations by Habchi et al. create the perfect storm for Aβ aggregation.

    While elevations of serum cholesterol during mid-life are known to elevate the risk for developing AD later in life, what triggers the full-blown condition and the onset of dementia, later in life, remains a known unknown, or perhaps even worse, an unknown unknown.


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    View all comments by Mike Miguel Pappolla

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  1. Cholesterol Greases the Aβ Aggregation Machine