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Stanford University School of Medicine

Alzheimer’s puzzle pieces are coming together

8541242629_2813230707_oThere's a lot we don't know about Alzheimer's disease. Here's some of what we do know: Its early stages are marked by the wholesale destruction of synapses -- junctions where neurons relay impulses from one cell to the next. As the condition progresses, whole nerve cells and even entire nerve circuits in the brain start to die off.

Why this happens is anybody's guess (or anybody's hypothesis, if you're a scientist). It's been long held that the culprit is a substance called A-beta, which can clump into sticky aggregates called beta-amyloid plaques in aging or diseased brains. The development of these plaques tends to track the progression of Alzheimer's but, lately, they've been suspected to be mere byproducts of a more pernicious process: the real damage caused by small, still-soluble A-beta clusters.

Maybe. But that's just a piece of an immensely complicated puzzle. Now, a study in Proceedings of the National Academy of Sciences by Stanford's Ben Barres, MD, PhD, and colleagues has tied A-beta to another bête noire of Alzheimer's: a hugely studied but still mysterious fatty-substance-conveying molecule called ApoE.

ApoE, in humans, comes mainly in three versions: ApoE2, ApoE3 and ApoE4. (Fourth and fifth versions ApoE1 and ApoE5 are rare, so most medical researchers don't sprain their brains worrying about them.) We each get dealt two copies of the gene coding for ApoE, so you can be a 3/3 (the most common), a 2/3, a 3/4, etc., meaning that you can have a mix of these protein types. What makes ApoE intriguing is that the combination of ApoE versions you have can greatly influence your chances of developing Alzheimer's disease.

Nobody's yet come up with a slam-dunk explanation of why which ApoE combo you get looms so large as a risk factor for Alzheimer's. It may be because neuroscientists have been so focused on neurons -- the brain cells that give their field its name, but which account for only one in 10 brain cells  -- they've overlooked neurons' roommates: astrocytes, the most common cells in the brain.

More than a third of all brain cells are astrocytes, star-shaped beauties whose more subtle functions have only recently begun to be fully appreciated. Barres' group showed a few years ago that, unexpectedly, astrocytes are constantly nibbling on synapses throughout development and adulthood, in a use-it-or-lose it fashion: busy synapses spared, unused ones eaten. Unused synapses that escape gobbledom become decrepit.

In another study, Barres and his associates found that a protein called C1q starts popping up on the surfaces of decrepit synapses as we age, rendering them increasingly vulnerable to getting chewed up by entirely different brain cells (called microglia) when the aging brain comes under inflammatory fire due to infection, head injury, a series of small strokes -- or, tellingly, exposure to soluble A-beta clusters. The first brain regions showing dramatic increases in C1q are precisely those most vulnerable to neurodegenerative diseases like Alzheimer's.

Barres' newest study shows that different ApoE versions variously speed up or slow down the rate at which astrocytes thin the herd of unused synapses, with the "good" version (ApoE2) doing the best job of preventing C1q buildup and the "bad" version (ApoE4) doing the worst. The study suggests that speeding up astrocytes is a good thing, as APoE2, a whiz at clearing slacker synapses and preventing C1q accumulation, is correlated with a lower Alzheimer's risk, while slowpoke ApoE4, which leaves a host of C1q-prone synapses in its wake, leads to a higher Alzheimer's risk.

Barres thinks efficient induction of unused-synapse clearance by astrocytes leaves surviving synapses relatively C1q-free, later in life. So, when an aging brain experiences an injury, infection, or cutoff of blood supply (as happens to most of us eventually), there's not much "tinder" (Cq1-rich synapses that should long since have been munched out of existence) to feed an inflammatory forest fire of indiscriminate synapse-snuffing microglia (aided, ironically, by astrocytes, which take on a sketchier character when inflammation is present) that wipes out working synapses and slacker synapses alike.

"The pieces are starting to come together," Barres says.

Previously: Stanford's brightest lights reveal new insights into early underpinnings of Alzheimer's,  Star-shaped cells nab new starring role in sculpting brain circuits, Protein known for initiating immune response may set our brains up for neurodegenerative disorders
Photo by Mon CEII

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