Does ApoB mediate motor neuron degeneration in sporadic amyotrophic lateral sclerosis?

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A new publication by Jamie K Wong, and colleagues including two well known ALS scientists argues apolipoprotein B-100 in sporadic amyotrophic lateral sclerosis CSF is the putative agent responsible for inducing motor disability, motor neuron degeneration and pathological translocation of TDP-43.

While there are publications with similar claims about every week, this one sounds impressive, the scientists here have really worked hard to make sure they haven't left any stone unturned.

For a layperson like me, at first glance, this publication makes sense as there is a special relation between ALS and lipid metabolism. Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fats, cholesterol and fat soluble vitamins) to form lipoproteins. They transport lipids in blood, cerebrospinal fluid and lymph. There are multiple classes of apolipoproteins and several sub-classes

ApoD level increases in nervous system with a large number of neurologic disorders inclusive of Alzheimer's disease, schizophrenia, and stroke. ApoE has been implicated in dementia and Alzheimer's disease.

So why not ApoB and ALS? Moreover overproduction of apolipoprotein B can result in lipid-induced endoplasmic reticulum stress and insulin resistance in the liver. ER stress leads to mislocalized misfolded proteins in cytosol, and half of ALS patients exhibit insulin resistance. In addition patients with ALS have higher levels of LDL-C, ApoB, and ApoB/ApoAI ratio already 20 years before diagnosis.

Yet this is not a study on humans but on mice and motor neurons in-vitro, and as usual a lot could be said about mice animal models of ALS. So maybe their claim, that ApoB is the agent responsible for inducing sporadic ALS, needs more work.

In addition a recent publication claimed that ALS patients that have elevated levels of ApoB in blood are associated with a lower risk of death. ApoB is also correlated with LDL (the "bad" cholesterol). Another study claimed the contrary. Yet another study did not find any evidence of association between lipoprotein or apolipoprotein levels and clinical findings.

There is also a lack of associations of cholesterol-lowering drugs (which lowers ApoB), antihypertensive drugs, and antidiabetics with the risk of ALS.

So we must remain cautious again, anyway even if this finding about ApoB and ALS was true, a commercial drug would be available only in 10 or 20 years.

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