Aß Dimers- The Long-Sought Minimal Culprit in Alzheimer's Disease?

Following on the heels of the headline-making Nature publication that demonstrated that NSAIDs (Non-steroidal AntiInflammatory Drugs) uniquely targeted a substrate (APP) rather than an active site of the gamma-secretase complex involved in plague formation in Alzheimer's (see Discount Thoughts for a great summary) comes a paper that may turn out to be one of the important papers in the history of Alzheimer's disease (AD) research.

Since 1905 when Alois Alzheimer first detected the symptoms of what we today call AD and identified the characteristic plaques that form in the brains of AD patients, the "amyloid hypothesis" has become almost synonymous with AD. For decades now, insoluble amyloid plaques, later found to consist of 40 (Aß 1-40) and 42 (Aß 1-42) residue oligopeptides, have been thought to be the hallmark of AD. Indeed, amyloid has become the poster boy for diseases caused by protein misfolding. Say "protein misfolding", and college students will pipe up and say "Alzheimer's"

However, the truth as usual has been complicated. In the last few years, attention has been shifting from the insoluble Aß to soluble forms of the peptide that are apparently in equilibrium with the aggegated beasts. Many oligomers have been isolated through antibody labeling and their toxicity has been demonstrated to various extents under various conditions. The "amyloid hypothesis" has become much more complex than before, and one of the original questions- whether these insoluble plaques are really the cause or just a manifestation of AD- has raised its head even more.

Recently exciting progress has been made in the field, with everything from metals to free radicals being implicated in the dementia and neuronal death that AD causes. On a wall in my room I have a Sigma Aldrich poster displaying a huge schematic of the principal species and pathways involved in AD, and one look at the poster clearly indicates how convoluted the whole scenario is. One of the continuing main reasons for slow progress has been the lack of structural information, with amyloid itself not being crystallizable and soluble species by definition being hard to structurally nail down.

But in light of the connection to soluble oligomers unearthed for AD, one lingering question has been foremost on everyone's minds- What is the minimal soluble species responsible for the symptoms of AD? Now it seems that a paper might go a long way in answering this question.

The short answer is "dimers dimers dimers". For the long answer, read the Nature Medicine paper. Charles Selkoe, Ganesh Shankar and others at Harvard separated different Aß species, insoluble and soluble, from the brains of AD patients. They then performed detailed characterization through immunoprecipitation, Western blots and other techniques, and then injected these fractions into rats, documenting which species can be identified as being the minimal as well as dominant contributors to the pathophysiology of AD.

I am no neurologist (paging Retread) but the researchers seem to have focused on three indicators of "brain damage"- an adverse effect on LTP (long-term potentiation); Wikipedia defines this as "the persistent increase in synaptic strength following high-frequency stimulation of a chemical synapse" which seems to indicate the fidelity of synaptic communication and a contributor to memory, LTD (long-term depression) which is the weakening of a synapse, and a decrease in dendritic spine density.

The researchers clearly find that dimers displaying a mass band of 8kD (confirmed by mass spectrometry) provide the greatest effect on these three parameters. Monomers and other soluble oligomers were not just less toxic but inactive. They also performed the interesting experiment of treating insoluble Aß cores with formic acid, this causing some of it to dissociate into dimers. This concoction proved deadly for rat brains, while the original untreated assembly did not prove as toxic. To make sure that the dimers were pure, they also used synthetic Aß dimers and obtained the same results. These set of results are pretty conclusive in demonstrating the toxicity of dimers.

As an interesting sidepoint, the authors also demonstrate the role of the metabotropic glutamate and NMDA receptors in facilitating the symptoms.

The significance of these results are clear. The authors themselves say "Our findings fulfill an essential requirement for establishing disease causation in Alzheimer’s disease". Many questions still remain though. We still don't know the molecular mechanism through which these dimers finally lead to neuronal death. Do they exert their effects by binding to metals like copper or iron? Do they slide into neuronal membranes and cause them to disintegrate? What other species do they actually go through before they cause harm? All these effects have been suggested as part of the list of effects responsible for neuronal damage. Which effects do Aß dimers fit into?

But all this is later. For now it's a significant achievement that we seem to have a handle on the minimal species responsible for AD. It's a staggeringly simple (or not...) structure involved in the progression of a set of maddeningly complex events. This finding seems to open a whole new window of experiments, conjectures and principles related to Aß dimers and AD in general.

My compliments to the team.

1. Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I., Brett, F.M., Farrell, M.A., Rowan, M.J., Lemere, C.A., Regan, C.M., Walsh, D.M., Sabatini, B.L., Selkoe, D.J. (2008). Amyloid-ß protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Medicine DOI: 10.1038/nm1782

2. Halliwell, B. (2006). Oxidative stress and neurodegeneration: where are we now?. Journal of Neurochemistry, 97(6), 1634-1658. DOI: 10.1111/j.1471-4159.2006.03907.x

3. Bush, A.I. (2003). Copper, ß -amyloid, and Alzheimer's disease: Tapping a sensitive connection. Proceedings of the National Academy of Sciences, 100(20), 11193-11194. DOI: 10.1073/pnas.2135061100

4. Kukar, T.L., Ladd, T.B., Bann, M.A., Fraering, P.C., Narlawar, R., Maharvi, G.M., Healy, B., Chapman, R., Welzel, A.T., Price, R.W., Moore, B., Rangachari, V., Cusack, B., Eriksen, J., Jansen-West, K., Verbeeck, C., Yager, D., Eckman, C., Ye, W., Sagi, S., Cottrell, B.A., Torpey, J., Rosenberry, T.L., Fauq, A., Wolfe, M.S., Schmidt, B., Walsh, D.M., Koo, E.H., Golde, T.E. (2008). Substrate-targeting gamma-secretase modulators. Nature, 453(7197), 925-929. DOI: 10.1038/nature07055