Amyloid precursor protein and autism

A cobbler should stick to his last. Meaning that people should generally stick to what they know and do best. I think most people would feel comfortable with this phrase. We would after all never (knowingly or willingly) go for surgery at a bakery or have our teeth fixed by a plumber. Likewise I probably wouldn't want my doctor to butcher my pork chops, even if she was handy with a scalpel.

I hope that I am not getting too out of my depth with this quite biochemistry-heavy post on some new findings on the amyloid precursor protein in relation to autism spectrum conditions. I have consulted with a few people who know a little more about this than I, just to check a few facts, but please do not assume I am an expert in this area. We will see if I do the science and research justice.

I start with some definition and description. Those with a medical or scientific background or possibly some family experience will probably already have heard of amyloid precursor protein (APP) in relation to Alzheimer's disease (AD). AD is the most common cause of dementia and the condition's profile is being elevated by people such as Sir Terry Pratchett (he of the Discworld novels). Without going too deeply into AD, the characteristic brain pathology of the condition is noted by the presence of neurofibrillary tangles and amyloid plaques. The plaques are made up of certain accumulated breakdown products of APP.

Nobody really knows how such pathology comes about in terms of genes and environment, but amongst the various investigations being undertaken into AD, one of the more widely suggested hypotheses involves APP and in particular, its peptide fragments, beta-amyloid, which are the main constituent of the plaques found in AD. Like any peptide, beta-amyloid is formed as a result of enzymatic processes involving a protease acting on APP, specifically the beta- and gamma-secretases. There are various other processes involved in this chain of events potentially related to AD but that's as far as I am going for now. I would perhaps also mention about the various pharmacotherapeutic measures currently available to tackle AD, based around two main classes of drug: the acetylcholinesterase inhibitors, which increase acetylcholine (often depleted in AD) and the glutamate-blocker, memantine.  I have talked about acetylcholinesterase inhibitors previously in relation to autism (here). I note that memantine has also been trialled in cases of autism with some indications of positive symptom response.

A recent paper by Ray and colleagues* (open access copy available here) looked at some of the products of amyloid precursor protein (APP) in plasma from people with autism. The paper is a quite complicated one and not the easiest piece to follow, hence my use of bullet-points to break the methods and selected findings down:

• A total of 39 participants were included for study: 15 diagnosed with severe autism (CARS score of 37+), 6 with mild-moderate autism (CARS: 30-36.5) and 18 asymptomatic controls. There was no significant difference across the mean ages of the groups.
• Various measures of the residues and peptides derived from APP in plasma were analysed alongside levels of brain-derived neurotrophic factor (BDNF). The main reason seems to be the study's focus on BDNF and specific APP breakdown products being neurotrophic (related to neuronal growth or survival) on the back of the data looking at head circumference in autism.
• There was no significant difference across the groups in terms of the mean total of total secreted amyloid precursor protein (sAPP) (that is the combined species based on the actions of the various forms of the secretase on APP).
• Levels of sAPP-alpha, the residue of the non-plaque associated form of APP, were elevated in the more severely affected autism group compared with controls.
• Levels of sAPP-beta, the residue associated with plaques from APP, were reduced in the more severely affected autism group compared with controls.
• Levels of the beta-amyloid peptides involved in plaque formation, including the most insoluble and toxic peptide, beta-amyloid-42, were also reduced in the more severely affected autism group compared with controls.

These are interesting findings. Plasma levels of beta-amyloid peptides (particularly 42) are associated with cognitive decline and onset of AD. I would however caution before making too many statements about the study results and risk of AD based on things like the small participant numbers included in the current study, and also their young age.

This is not the first time that this particular research group have published in this area. Indeed in a previous study based on even smaller participant numbers, they reported increased total sAPP in severe autism relative to other groups and controls; contrasting with no overall difference in the current study. Perhaps more interesting however was the confirmation from the recent study of higher levels of non-plaque related sAPP combined with lower levels of plaque-related beta-amyloid-40 peptide in severe autism. Likewise another group has confirmed some of theses findings.

I would like to believe that there may be some good sense in conducting further, large-scale study of levels of sAPP-alpha in autism which some have suggested might be a potential biomarker for autism. There are also a few other potential tie-ins to sAPP-alpha which might also necessitate some further investigation including a peripheral nicotinic effect, the use of statins, and the effect of selected neuropeptides.

As per my initial caveat, I would perhaps advise interested readers to do a little confirmatory reading before taking my observations as any kind of truth. If on the other hand you need someone to name your Star Wars villains, well I'm yer man..

* Ray B. et al. Increased secreted amyloid precursor protein-α (sAPPα) in severe autism: proposal of a specific, anabolic pathway and putative biomarker. PLoS ONE. 2011: 6:6