From Aging, to Aβ, to Tau—Is Cholesterol the Link in Alzheimer’s

Researchers have linked the most important risk factor for Alzheimer disease, advanced age, to AD’s two pathological hallmarks, amyloid-β plaques and tau tangles in the brain. The three are tied together by membrane cholesterol and calcium signaling, according to a cell biology paper published April 8 in the Journal of Neuroscience. Scientists at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, propose a model in which increased membrane cholesterol allows Aβ to alter calcium influx and activate the enzyme calpain to slice tau into toxic pieces.

As you age, increased cholesterol might make your hippocampal neurons more susceptible to the toxicity, said Alexandra Nicholson, first author on the paper. Principal investigator Adriana Ferreira had previously shown that Aβ caused calpain to cleave tau, releasing a 17 kiloDalton fragment that caused degeneration of cultured neurons (Park and Ferreira, 2005). In the current work, we basically just moved upstream of this fragment, Nicholson said, seeking the reason that tau would be selectively truncated in older cells.

Nicholson isolated hippocampal neurons from embryonic rats and cultured the cells for one to three weeks. Over that time, the cells transition from expressing embryonic splice forms of tau to the mature forms. Older cells were more susceptible to Aβ: when incubated with pre-aggregated amyloid, the seven- and 12-day-old cultures showed no effect, whereas 17- and 21-day-old cells exhibited membrane blebbing and retraction of processes, and a greater percentage of dead cells. Concomitant with the degeneration of older cultures was the presence of the 17-kDa tau fragment. In older cultures, Aβ also caused increased activity of calpain, the scientists showed, via its cleavage of spectrin, another calpain substrate.

Calpain binds lipids and requires calcium for its activation, so Nicholson looked to the cell membrane and calcium levels to explain the enzyme’s enhanced activity. Cholesterol is involved in mediated membrane calcium influx, and has also been linked to Alzheimer disease. For example, ApoE, some forms of which carry an increased risk of AD, transports cholesterol in the central nervous system. Calcium dysregulation has also been linked to Alzheimer’s; soluble Aβ may increase calcium intake by causing oxidative stress or forming a membrane pore that allows the ion through (for review, see Bezprozvanny and Mattson, 2008). Using microscopy and biochemical assays, Nicholson found that the mature neurons had about a 150 percent increase in membrane cholesterol compared to the younger cells. Similarly, in rats hippocampal cholesterol content increased from 23 nanograms of cholesterol per microgram of protein in one-day-old animals to 68 ng/μg protein in three-month-old rats.

If high membrane cholesterol promotes tau cleavage, the scientists reasoned, then taking away that cholesterol should protect cells. Nicholson used methyl-β-cyclodextrin (MBCD) to wick away the cholesterol in old neurons. MBCD is a large sugar ring that can cage cholesterol and add or remove the lipid from a membrane, depending on cholesterol concentration. Three-week-old cultures treated with MBCD and Aβ did not show the tau and spectrin cleavage found in cells treated with Aβ alone. While approximately 60 percent of Aβ-treated cells died, only half as many MBCD- and Aβ-treated cells died.

Next, Nicholson asked if the converse was true: Would adding cholesterol to young membranes cause them to respond to Aβ like the mature ones Again, she used MBCD, this time complexed with cholesterol so it would add the lipid to the cell membranes of week-old cultures. Under these conditions, Aβ caused cleavage of both tau and spectrin, indicating calpain activity.

The results led Nicholson and Ferreira to suspect that calpain mediated tau cleavage in response to cholesterol, but they sought more direct evidence by examining calcium levels in their cultures. Using the fluorescent dye fura-2 that indicates the presence of calcium, they found that adding Aβ to mature cells tripled intracellular calcium in comparison to controls. Young, or cholesterol-depleted, neurons were unaffected.

The study links AD lesions, Aβ, and tau, to the increased membrane cholesterol and intracellular calcium that come with aging, Nicholson said. She is currently treating cells with cholesterol-altering drugs to discover how cholesterol influences Aβ vulnerability. It will also be important to confirm these findings in an animal, as opposed to a cell culture dish, Nicholson said.

The work is an important advance that dovetails nicely with previous studies on how altered lipid and calcium regulation endangers cells, according to Mark Mattson of the National Institute on Aging in Baltimore, Maryland, who was not involved in the current study. Lowering cholesterol levels through dietary modifications, exercise, and statins may therefore stabilize cellular calcium homeostasis and so protect neurons against dysfunction and degeneration in aging and AD, he wrote in an e-mail to ARF.

Nicholson AM, Ferreira A. Increased membrane cholesterol might render mature hippocampal neurons more susceptible to beta-amyloid-induced calpain activation and tau toxicity. J Neurosci. 2009 Apr 8;29(14):4640-51. Abstract. Abstract

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