Alzheimer's: Wnt or Lose

A molecular exploration of the causes of Alzheimer's disease.

What causes Alzheimer's disease remains a bit of a mystery, as there is no simple and single molecular explanation, as there is with, say, Huntington's disease, which is caused by a single gene defect. There is one leading candidate, however, which is the amyloid protein, one of the accumulated molecular signatures of the disease in post-mortem brains. Some genetic forms of Alzheimer's start with defects in the gene that encodes this protein, APP (amyloid precursor protein). And a protease processing system that cleaves out the toxic amyloid beta protein from the much larger original APP protein is also closely involved with Alzheimer risk. So while there are many other genetic risk factors and possible causes relating to the APP and other systems, this seems to be the dominant causal element in Alzheimer's disease.

The naming of this protein is rather backwards, focusing on the pathological roles of defective forms, rather than on what the normal protein does. But we don't really know what that normal function is yet, so have had little choice. A recent paper described one new function for the normal APP protein, which is as a receptor for a family of proteins called WNT (for wingless integration site, an obscure derivation combining findings from fly and mouse genetics). APP had long been known to interact with WNT functions, and a reduction of WNT signaling is one of the pathologic (and possibly pathogenic) hallmarks of Alzheimer's, but this seems to be the first time it has been tabbed as a direct receptor for WNT.

What is WNT? These proteins track back to the dawn of multicelled animals, where they first appear in order to orchestrate the migration and communication of cells of the blastopore. This is the invagination that performs the transition (gastrulation) from an egg-derived ball of cells to the sheets of what will become the endoderm and mesoderm on the inside, and the ectoderm on the outside. The endoderm becomes the gut and respiratory organs, the mesoderm becomes the skeleton, muscles, blood, heart, and connective tissue, and the ectoderm becomes the skin and nervous system. WNT proteins are the ligands expressed in one set of cells, and their receptors (Frizzled and a few other proteins) are expressed on other cells which are nearby and need to relate for some developmental / migration / identification, or other purpose. One other family, the NOTCH proteins and their respective cell surface receptors, have a similar evolutionary history and likewise function as core developmental cell-cell signaling and identification systems. 

Rough structure of the APP protein. The membrane  spanning portion is in teal at the bottom, showing also some key secretase protease cleavage sites, which liberate alpha and beta portions of the protein. The internal segment is at bottom, and functions, when cleaved from the rest of the protein, as a nuclear transcription activator. Above are various extracellular domains, including one for "ligand binding", which is thought by at least one research group to bind WNT. The dimerization domain can bind other APP proteins on other cells, and heparin, another binding partner is a common component of the extracellular environment.

Fast forward a billion years, and WNT family members are deeply involved in many decisions during animal development and afterwards, particularly in the brain, controlling nerve cell branching and synapse formation in adults. WNT, NOTCH, and APP are each ligand+receptor systems, where a ligand from one cell or in soluble form binds to a receptor on the surface of another cell, which "receives" the signal and can do a multitude of things in response. The usual receptors for WNT are a family of Frizzled proteins plus a bunch of other helper proteins, the receptors for NOTCH are Jagged proteins, and the APP protein is itself a receptor whose ligand has till now been unclear, though it can homodimerize, detecting APP on other cells. APP is a large protein, and one of its responses to signals is to be cleaved in several ways. Its short cell-interior tail can be cleaved, (by gamma secretase), upon which that piece travels to the nucleus and with other proteins acts as a transciption regulator, activating, among other genes, its own gene, APP. Another possible cleavage is done by alpha secretase, causing the release of soluble APP alpha (sAPPα), which has pro-survival activities for neurons and protects them against excessive activity (excito-toxicity). Lastly, beta-secretase can cleaves APP into the toxic beta (Aβ), which in tiny amounts is also neuro-protective, but in larger amounts is highly toxic to neurons, starting the spiral of death which characterizes the hollowing out of the brain in Alzheimer's disease.

The cleavages by alpha secretase and beta secretase are mutually exclusive- the cleavage sites and products overlap, so cleavage by one prevents cleavage by the other, or destroys its product. And WNT signaling plays an important role in which route is chosen. WNT signals by two methods, called canonical or non-canonical, depending on which receptor and which ligand meet. Canonical signaling is neuro-protective, opposed to Alzheimer development, and leads to alpha secretase cleavage. Non-canonical signaling tends to the opposite, leading to internalization of APP from the surface, and beta secretase cleavage which needs acidic conditions that are found in the internal endsomes where APP ends up. So the balance of WNT "tone" is critical, and is part of the miscellaneous other risk factors that make up the background for Alzheimer's disease. Additionally, cleavage by gamma secretase is needed following cleavage by beta secretase in order to make the final forms of APP beta. The gene for gamma secretase is PSEN1 (presenilin-1), mutations in which are the leading genetic cause of Alzheimer's disease. Yet these mutations have no clear relation with the activity of the resulting gamma secretase or the accumulation of particular APP cleaved forms, so this area of causality research remains open and active.

But getting back the WNT story, if APP is itself a WNT receptor, then that reinforces the centrality of WNT signaling in this syndrome. Indeed, attempts to treat Alzheimer's by reducing the toxic amyloid (APP beta) build up in various ways have not been successful, so researchers have been looking for causal factors antecedent to that stage. One clue is that a key WNT inhibitor, DKK (for dick-kopf, derived from fly genetics, which have had some prominent German practitioners), has been experimentally an effective therapy for mice with a model form of Alzheimers. DKK is an inhibitor of the canonical WNT pathway, (via the LRP6 co-receptor of Frizzled), shunting it towards more non-canonical signaling. This balance, or "tone" of WNT signaling seems to have broad effects in promoting neurite outgrowth and synapse formation, or the reverse. Once this balance is lost, APP beta induces the production of more DKK, which starts a non-virtuous feedback cycle that may form the core of Alzheimer's pathology. This cycle could be started by numerous genetic defects and influenced by other environmental risk factors, leading to the confusing nature of the syndrome (no pun intended!). And of course the cycle starts long before symptoms are apparent and even longer before autopsy can verify what happened, so getting to the bottom of this story has been hugely frustrating.

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