Alzheimer's Disease is the most common form of dementia, affecting more than 400,000 people in the U.K. and some 5.5 million in the U.S. The disease has a characteristic pathology, which often appears first in the hippocampus, and then spreads to other regions of the brain. This is accompanied by impairments in cognition, with cell death and loss of connections leading first to deficits in memory and spatial navigation, and then to global dysfunction.
The exact cause of Alzheimer's is not known, but a number genes have been implicated. One of these encodes a protein called amyloid precursor protein (APP), which can be broken down into fragments. One of these fragments is insoluble, and when deposited accumulates to form the senile plaques that are characteristic of the disease. It is widely held that this fragment is toxic, and that plaque formation causes cell death.
A new study published last week in Nature may lead us to look at the pathogenesis of Azheimer's in a new light. It provides evidence that the degeneration which is characteristic of the disease occurs when a cellular self-destruction mechanism which normally occurs during neural development is re-activated.
The human brain is an incredibly complex structure, containing an astronomical number of neurons - hundreds of billions - and something like one quadrillion connections, or synapses. As the brain develops, huge numbers of nerve cells are generated by cell division from proliferative tissues lining the structures which will eventually form the lateral ventricles. These newborn cells migrate from their place of birth and, once they arrive at their final destination, begin to extend their axons and dendrites, which then form connections with other cells. Some neurons form only a few connections, whereas others, such as the Purkinje cells in the cerebellum, form hundreds of thousands.
Mother Nature evolved various strategies to overcome the logistical problems of growing such a complex organ. One of these is the massive over-production of neurons: many more are generated than are needed for a mature, fully functional brain, then large numbers are culled by a process called programmed cell death (apoptosis), which begins early on in neural development, and continues throughout life. Another strategy is over-abundance of connections: the cells form many more synapses than are needed, and inappropriate or extraneous connections are subsequently "pruned", so that only those which have properly formed remain in place.
Degeneration is, therefore, a normal part of brain development. The mechanisms of programmed cell death have been studied extensively, and we have some understanding of how it occurs. The death pathway begins with a biochemical signal, which initiates a series of structural changes in the cell. The membrane starts to bulge irregularly; proteins are destroyed; the nucleas disintegrates and the DNA inside it is fragmented. The cell shrinks then falls apart, and the debris are cleared away. Many of these processes are mediated by enzymes called caspases. However, blocking these enzymes only inhibits the degeneration of cell bodies, so axonal degeneration is thought to occur by a caspase-independent mechanism.
We also know that cells die for different reasons.The survival of dorsal root ganglion cells, for example, is dependent upon a supply of a nourishing substance derived from the muscle target. These cells migrate out from the top of the spinal cord, and come to rest just outside it before extending a single process which splits in two branches (or "bifurcates"). One branch projects back into the spinal cord, while the other extends a longer distance, out to a specific muscle in the limb or body wall. In the 1940s, Rita Levi-Montalcini identified the substance which sustains these cells: a protein called nerve growth factor (NGF). She also showed that the supply of NGF is limited; axons entering the muscle compete for it, so that those which do not receive the signal perish and die.
In the new study, Anatoly Nikolaev and Marc Tessier-Lavigne of the San Francisco-based biotechnology company Genentech, in collaboration with researchers from Salk Institute in La Jolla, examined the expression patterns of proteins called tumor necrosis factor receptors (TNFRs) in the emryonic mouse nervous system. These proteins bind to and are activated by tumor necrosis factor, a small molecule which is primarily involved in regulating the activity of cells in the immune system. This molecule was initally identified by (and named for) its ability to inhibit the growth of tumors by inducing apoptosis in cancerous cells. TNFRs, whose activation leads to the induction of apoptosis, are also referred to as death receptors.
Nikolaev and his colleagues observed that one of the receptors, death receptor 6 (DR6) is expressed at low levels in dividing cells in the spinal cord, and that it is abundant in the cell bodies and axons of newborn cells in the spinal cord and dorsal root ganglia, at the time when some of them are about to undergo apoptosis. They therefore isolated spinal cord cells and grew them in a culture dish. Normally, cells can survive for 24 hours under these conditions, but then start to die off unless the appropriate growth factor is added to the culture medium. But the researchers found that inhibiting DR6 activity, either by RNA interference or with antibodies, considerably delayed apoptosis, even in the absence of the growth factor. Cells from mutant mice in which the DR6 gene has been deleted were likewise protected against death.
Next the researchers explored possibility that DR6 is involved in axonal degeneration. To do so, they grew dorsal root ganglion cells in compartmentalized chambers, such the axons extending from a cell body in central chamber grow under a partition into a side chamber. In this set-up, the movement of fluids between the chambers is limited, so the micro-environment within each chamber can be manipulated separately. In these experiments, removal of NGF from the side chamber led 24 hours later to degeneration of the axons, but not to cell death, because the central chamber contained the growth factor. However, when DR6 activity was inhibited, the axonal degeneration was delayed.
But does DR6 initiate axon degeneration in living animals as well as in cltured cells? To answer this question, the researchers looked at the connections in the visual pathway of normal mice, and compared them with their DR6 mutants. In the course of normal development, axons leaving the retina enter the optic nerve and some of them branch off to form synapses in the superior colliculus, a small structure in the brain which is involved in generating eye movements. Many of these axons overshoot their target areas, and form inappropriate connections, but are then pruned. In the mutant mice, however, the redundant synapses remained in place, and as a result the bundles of axons in the pathway were thicker.
DR6 is an orphan receptor - that is, the molecule which binds to and activates it has not yet been identified. But the researchers speculated that APP, the protein implicated in Alzheimer's may bind to it, because it too is implicated in degeneration and also has a very similar expression pattern. Sure enough, a series of biochemical assays showed that a small fragment of APP interacts with a region of DR6 that is located on the outside of the cell. When growth factors were withdrawn from neurons growing in a culture dishes, the density of APP at the cell membrane was seen to decrease before cell death occurred. However, apoptosis could be prevented if the APP fragment was neutralized with an antibody. The appearance of connections in mutant mice lacking the APP gene were found to be similar to those in DR6 mutants, suggesting that the two proteins interact in live animals.
Thus, an interaction between APP and DR6 regulates both apoptosis and axonal degeneration - read "pruning" - in several differnt types of embryonic neurons, both in the culture dish and live mice. The findings of this study point to an APP-death receptor mechanism that occurs during development, in which malnourishment causes APP, which is normally associated with the membrane, to be broken down into fragments. One of the fragments generated then binds to DR6, and the cell death pathway is initiated, with axonal pruning and cell death being triggered by distinct caspase enzymes. And so it seems that the cell death and degeneration that occurs during development is recapitulated in the disease process. Just as the mind of the Alzheimer's reverts to a child-like state, so too does the brain.
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Nikolaev, A. et al (2009). APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457: 981-989. DOI: 10.1038/nature07767
What is the full name of the write "Mo"? I really need the full name for my college research paper citation page.
Very interesting, it adds another mechanism through which cleavage of APP is involved in Alzheimers. I'd also point out that in addition to the amyloid plaques quite a lot of evidence has emerged recently that points to a role for soluble Abeta-derived diffusible ligands (ADDLs) which are also produced by cleavage of APP, but appear to exert their neurotoxic effect through a different mechanism to the proposed N-APP/DR6 pathway.
All in all the evidence is mounting that improper activity by APP derivatives plays a key role in the early development of Alzheimers, and that much of the damage may be initiated well before the amyloid plaques appear.
Middle-age people whose parents had Alzheimer's and who carry the so-called Alzheimer's gene might very well have the memory of someone 15 years older, a new study has found.
This memory decline was not detected in people of middle age whose parents had Alzheimer's but who do not carry the gene, known as ApoE4, according to the study.
There's another interesting paper in Nature this week that hints at how amyloid-Î² peptides damage neurons.
Nature news has a summary.
Very nicely written. Very informative. Thanks for sharing.
Interesting. What could account for wide-spread, progressive, similar end effects across neurological contexts?
Hi! Thanks for contributing this to the latest Encephalon blog carnival - now all up here! :)http://podblack.com/?p=1266