Alzheimer’s research has blamed accumulations (plaques) of mis-folded proteins (amyloid-β) for damaging neurons, causing cognitive decline. But maybe not. Instead, leakage from the brain’s tiny blood vessels may be the cause. Plaques may be a consequence. This is startling. It may redirect Alzheimer’s research towards blood vessels. Other neurodegenerative diseases (Parkinson’s for instance) may look there too. This might be good news, since vascular defects can be repaired by drugs, while Alzheimer’s is untreatable now.
The tangled placques are depicted vividly, as here:
Alzheimer’s might begin, this report suggests, in cells sheathing the tiny blood vessels weaving among brain cells. The sheath is the “blood brain barrier” (BBB). It’s normally tough and impenetrable to drugs and pathogens. The blood vessels inside BBB sheaths supply oxygen and energy to brain cells and carry away metabolic waste. Here’s an image of the BBB:
A genetic defect studied here, however, weakens the sheath, and is found in many (but not all) Alzheimer’s victims. The defect creates an inferior variant of a protein whose normal form binds snugly onto the sheath cells, armoring them against chemical assaults triggered by another protein (called “CypA” here, abbreviating its chemical name).
The inferior variant binds loosely, not snugly, to the sheath cells. This opens crevices for CypA’s corrosions. They trigger inflammation and damage to BBB cells. (CypA’s benefits aren’t known, though it must have some elsewhere in the body.) With sheath damage come leaky blood vessels. Leaked blood then bathing neurons contains substances that fatally damage them. As neurons die, cognitive decline creeps in.
The key finding? BBB damage came first. Damage to brain cells followed. So perhaps it’s a weakened BBB and leaking blood that kills neurons, not the amyloid “plaques”. This would be good news, for drugs can inhibit CypA and its corrosions and let the BBB heal. Healing was seen in these experiments.
Now, the limitations: these findings are from experiments with mice. Mice were genetically engineered (at the fertilization stage) to incorporate the defective human gene that builds the inferior sheath-protecting protein. (Call that human gene “A4”, abbreviating its chemical name.) It was the mouse BBB that was damaged by the inferior protein produced by the human A4 gene.
Thus, despite the ingenuity of this research, it’s a result not yet duplicated in humans. So this work doesn’t prove that human A4 damages human BBB sheath cells. It is, however, highly suggestive, since human and mouse genes show strong similarities in many basic features. (That’s why mice are invaluable animals for medical research.) Also highly suggestive: human victims of neurodegenerative diseases such as Alzheimer’s and Parkinson’s also show blood vessel damage like that in these experimental mice.
“Highly suggestive” is great progress. It justifies examining vascular (i.e. blood vessels) systems in humans, searching for biological processes like those in the genetically engineered mice.
What phenomenon in nature?
Humans with neurodegenerative diseases have damaged blood vessels. They also often have a defective variant of one gene (A4) active in their blood-brain barrier (BBB).
What did this discovery show?
Mice engineered to posses the human A4 gene suffered damage to the BBB before their neurons were damaged. How A4 damages the BBB was also discovered.
What was known before?
The genetic defect A4 was associated with vascular defects, but it was unknown (i) how it caused them, and (ii) whether the defects preceded neuronal damage.
What remains unknown?
Whether blood vessel pathologies in fact cause neurodegenerative diseases in humans.
R. Bell, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A, 485 Nature, 512-516 24 May 2012.
P. Carmeliet and B. de Strooper, A breach in the blood-brain barrier, 485 Nature 451-452, 24 May 2012.