A possible physiological role of Abeta as a crosslinker

Although soluble oligomers are regarded as the most toxic aggregates of Abeta, the amyloidogenic nature of Abeta certainly is not accidental and should play a role in the still unknown physiological functions of Abeta. The testable hypothesis put forward here postulates that short Abeta oligomers can crosslink the neurotrophin receptor p75 with APP and other proteins and mediate a direct cooperation between them. Support for this hypothesis comes from reports about similar effects of p75 and APP and from the discovery that Abeta can specifically bind to the stalk domain of the receptor. The binding site is adjacent to the transmembrane region of p75 (and probably extends into it), similar to the homologous sequence of Abeta within APP which also binds Abeta. Stalkbound Abeta monoand dimers may induce the formation of membrane-associated oligomeric Abeta links between p75 receptors and APP, presumably catalyzed by gangliosides. Crosslinking of p75 and APP by Abeta facilitates a spatially and temporally stabilized interaction between the signal-transducing mechanisms of the two proteins upon p75 activation. The hypothesized cooperation of p75 with proteins such as APP, prion protein PrPc and alphasynuclein integrates part of their functionality into the dual growth and function control which is exerted by the neurotrophin receptors Trk and p75 and which modulates neuronal plasticity and more. However, Abeta-driven crosslinking can go awry when toxic amyloid species (of whatever kind) interfere with it or/and when the production of Abeta or a cooperation partner of p75 is unbalanced. Due to irregular activation of the p75 receptor, the normally fine-tuned neurotrophin receptor control system becomes dissociated and produces or increases degenerative effects. In particular, an excess of Abeta oligomers and fibrils causes among other effects unphysiological stimulation of p75 and APP and leads to aberrant neurite outgrowth, loss of synapses and neuronal death. Such processes indicate a critical role of p75 in certain amyloidopathic diseases. The binding of Abeta to the p75 stalk might provide a natural means of neutralizing toxic aggregates of Abeta and other amyloidogenic proteins, without affecting the physiological roles of p75 and Abeta. When activated p75 receptors and cooperating proteins undergo proteolysis and endocytosis, the amino acid sequence between the alphaand gamma-cleavage sites of p75 yields a proteolytic fragment F which overlaps or contains the stalk binding site for Abeta. If bound to an Abeta oligomer this fragment may direct the oligomer to degradation mechanisms while released F could act as an Abeta scavenger. Evolution might have honed the binding properties of F and its relative position within p75 in a way that permits the normal aggregation and function of membrane-anchored Abeta and obstructs the binding of floating Abeta and other amyloidogenic proteins to p75. In vitro experiments with a peptide fragment from F indicate that low concentrations of this fragment prevent p75 activation and apoptosis upon application of aged Abeta while p75 activation and short-term neurite outgrowth upon NGF stimulation remain largely unaffected. Aggregate types of amyloidogenic proteins can easily be tested if they activate p75 and if fragments of the p75 stalk prevent activation and apoptosis, and optimized derivatives of the extended stalk of p75 might be useful for the treatment of various amyloidopathic diseases. I. The neurotrophin receptor p75 and its ligands The structure of the neurotrophin receptor p75 The neurotrophin receptor p75, which is expressed by many cell types, is a transmembrane protein. Its extracellular part consists of a region with four cystein-rich domains (CRD) that serve as ligand binding site, and the largely unstructured stalk which connects the CRD region with the transmembrane domain. The intracellular part can be divided into the juxtamembrane and the "death domain". The death domain contributes to the apoptotic signaling of p75 and is in differential forms common to a class of "death receptors". p75 has a broad range of functions comprising trophic and apoptotic effects. Under certain circumstances, p75 activation leads to the cleavage of the extracellular domain by alpha-secretases and the shedding of the resulting N-terminal fragment, and to the following cleavage of the transmembrane domain by gamma-secretase. For the purposes of the present study, the term "extended stalk" designates the stalk and its adjacent transmembrane segment up to the gamma-secretase cleavage site (Figure 1). Neurotrophins and their receptors The main regular ligands of p75 are the neurotrophins; other regular ligands are the proneurotrophins and Nogo which, however, require the cooperation of p75 with additional receptors. The phylogenetically old neurotrophins are widely used within the animal kingdom, and mammals express four types of them: the nerve growth factor NGF, the brain-derived neurotrophic factor BDNF, the neurotrophin-3 NT3, and NT4/5 (NT4 and NT5 have been found to be identical). The neurotrophins are signal proteins that are released from certain cell types into the extracellular space and taken up by other or the same cells via the tropomyosin-related or tyrosine receptor kinase Trk receptors and the p75 receptor (also called p75NTR or p75 LNTR). Trk receptors bind their substrates in a relatively specific manner while p75 can bind all types of neurotrophins with about equal affinity. TrkA binds mainly NGF and with lower affinity also NT-3, TrkB binds BDNF and NT4/5, and TrkC binds NT-3. Neurotrophins were investigated first in the nervous system of mice and rats where they promoted growth and survival (hence the name "neurotrophin"). Later a number of other signal proteins with comparable effects were identified and named "neurotrophic factors". Since then the neurotrophins have been found in many types of tissues and cells and linked to a broad spectrum of effects. Neurotrophin stimulation dimerizes the Trk and p75 receptors, alters their conformation and initiates a transformation of associated membrane rafts (see III). Receptor activation leads to interactions of the intracellular receptor domain with certain membrane-bound and cytosolic proteins and thus triggers intracellular signal cascades which determine the receptor effects. While the Trk receptors have a mostly neurotrophic character the receptor p75 can exert both neurotrophic and apoptotic effects. The neurotrophins influence proliferation, growth, survival, differentiation, cell-specific function and regeneration. Depending on their spatial and temporal combination, the neurotrophins can act in rather variable and complex, cell type-specific ways and facilitate an individual control of cell populations within a complex cellular context. The variety of their effects makes it difficult to develop a unified concept of their functionality. Regular functions of p75 within the central nervous system The cooperation of Trk receptors and p75 constitutes a dual growth and function control that aims at the optimal integration of cells into their context (review Blöchl and Blöchl, 2007). This control is achieved by a gradual shift of the workings of p75 during continued stimulation with neurotrophins,