I first heard about Alzheimer’s Disease (AD) when I was about nine.  I remember the troubling feeling of how the condition takes hold, of how sufferers become a warped shadow of their previous selves.  Since then, AD has become more common.  This is mainly because the occurrence of heart disease and cancers, that kill humans earlier, have begun to fall.  This apparent increase in AD has motivated funding bodies to grant money to research focused on AD and related conditions.

Early examination of the corpses of patients with dementia found that most of the body was quite normal.  The damage appeared to be limited to the Central Nervous System (Brain and spine), where there were abnormal and typically rather long fibres.  Initially, these were thought to be made of starch, but it quickly became apparent that they were proteinaceous and the more recently, a mis-folded protein.  It’s not hard to guess that a build-up of a large amount of wrongly-built protein might get in the way of normal cellular activity.  Perhaps unsurprisingly, it also leads to cell death.  This loss of cells in the brain fits well with the decrease in cognitive function.  This decrease in ability to process information and remember things can be acute; the test does not look challenging to someone with normal cognition [1].

Since AD has become more common, its subtleties have begun to emerge.  For example, there are now well-recognised early- and late-onset types.  The early onset is regarded as familial because it is associated with inherited faulty genes.  Late-onset AD is associated with the loss of function of a different protein, called ABCA7.  This protein is a lipid transporter, and is therefore part of the system that moves lipids around the cell.

Moving lipids about the cell is useful because it ensures that the right ones are in the right place, but also means that the right lipids are made.  For example, cells that cannot transport PS to the mitochondria are entirely unable to make PE.  Not being able to make or transport PE can be a real problem for the cell.  For example, work completed in Japan over about three decades, showed that PE probably has a crucial structural role in cell division [2-7].  A cell that was unable to move it would not be able to divide.

Some very recent work has also shown that PE is an important component for ensuring the membrane has the correct physical properties for its function [8].  Furthermore, a study by Sakae et al. [9], that researched the lipid profile of mice who do not have working ABCA7 transporters showed that the amount of PE was about 36% lower in affected mice, against the control group.  As PE typically represents about 30% of the membrane, this may also represent an effective increase in the abundance of other lipids.  This may therefore effect a considerable change in the physical behaviour of the membrane, as the concentration of virtually all of the components will be changed.

This change in the lipid composition correlated with the type of memory loss observed in AD [9] and represents a nice insight into what role lipids may have in brain and spinal cord nerve activity.  The broader question now is, if this effect can alter the function of membranes so much, what would a smaller change do?  Effects of perhaps 75% activity of this transporter may be observable over a lifetime.  Certain diets or malnutrition may mean that particular membrane components may be less abundant or absent, leading to a significant difference in the physical behaviour of the membrane and therefore the cell.




[1] S. Srinivasan, Neurology India, 2010, 58, 702.  DOI: 10.4103/0028-3886.72167.

[2] S. Y. Choung, T. Kobayashi, K. Takemoto, H. Ishitsuka and K. Inoue, Biochimica et Biophysica Acta (BBA) – Biomembranes, 1988, 940, 180-187.

[3] K. Emoto, H. Inadome, Y. Kanaho, S. Narumiya and M. Umeda, Journal of Biological Chemistry, 2005, 280, 37901-37907.

[4] K. Emoto, T. Kobayashi, A. Yamaji, H. Aizawa, I. Yahara, K. Inoue and M. Umeda, Proceedings of the National Academy of Sciences, 1996, 93, 12867-12872.

[5] K. Emoto, O. Kuge, M. Nishijima and M. Umeda, Proceedings of the National Academy of Sciences, 1999, 96, 12400-12405.

[6] K. Emoto, N. Toyama-Sorimachi, H. Karasuyama, K. Inoue and M. Umeda, Experimental Cell Research, 1997, 232, 430-4.

[7] K. Emoto and M. Umeda, The Journal of Cell Biology, 2000, 149, 1215-1224.

[8] R. Dawaliby, C. Trubbia, C. Delporte, C. Noyon, J. M. Ruysschaert, P. Van Antwerpen, C. Govaerts, Journal of Biological Chemistry , 2016, 291, 3658–3667.  DOI: 10.1074/jbc.M115.706523

[9] N. Sakae, C. C. Liu, M. Shinohara, J. Frisch-Daiello, L. Ma, Y. Yamazaki, M. Tachibana, L. Younkin, A. Kurti, M. M. Carrasquillo, F. Zou, D. Sevlever, G. Bisceglio, M.Gan, R. Fol, P. Knight, M. Wang, X. Han, J. D. Fryer, M. L. Fitzgerald, Y. Ohyagi, S. G. Younkin, G. Bu, T. Kanekiyo, The Journal of Neuroscience, 2016, 36, 3848 –3859.