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J Physiol Volume 575, Number 1, 5-10, August 15, 2006 DOI: 10.1113/jphysiol.2006.111203
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Topical Review

Physiological roles for amyloid ß peptides

Hugh A. Pearson1 and Chris Peers2

Faculties of
1 Biological Sciences
2 Medicine and Health, University of Leeds, Leeds LS2 9JT, UK


   Abstract
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 Abstract
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Alzheimer's disease is recognized post mortem by the presence of extracellular senile plaques, made primarily of aggregation of amyloid ß peptide (Aß). This peptide has consequently been regarded as the principal toxic factor in the neurodegeneration of Alzheimer's disease. As such, intense research effort has been directed at determining its source, activity and fate, primarily with a view to preventing its formation or its biological activity, or promoting its degradation. Clearly, much progress has been made concerning its formation by proteolytic processing of the amyloid precursor protein, and its degradation by enzymes such as neprilysin and insulin degrading enzyme. The activities of Aß, however, are numerous and yet to be fully elucidated. What is currently emerging from such studies is a diffuse but steadily growing body of data that suggests Aß has important physiological functions and, further, that it should only be regarded as toxic when its production and degradation are imbalanced. Here, we review these data and suggest that physiological levels of Aß have important physiological roles, and may even be crucial for neuronal cell survival. Thus, the view of Aß being a purely toxic peptide requires re-evaluation.

(Received 7 April 2006; accepted after revision 22 June 2006; first published online 29 June 2006)
Corresponding author H. A. Pearson: Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK. Email: h.a.pearson{at}leeds.ac.uk

Aß formation

It is now over two decades since amyloid ß peptide (Aß) was first sequenced and recognized as a potential marker of Alzheimer's disease (Glenner & Wong, 1984). Soon after, this 39–43 amino acid peptide was identified as the major component of the extracellular plaques that define this major form of dementia (Wong et al. 1985). Since then a wealth of academic and commercial research has been aimed at understanding where this peptide comes from, for a very simple reason; if we can stop its production, we might also prevent Alzheimer's disease. Alzheimer's disease is a major problem, and one likely to grow with an ageing population since it is primarily a disease of old age. The intensity and volume of dedicated research has resulted in a detailed current understanding of Aß production which is summarized in Fig. 1. In essence, Aß is a cleavage product of a large, transmembrane protein, termed APP (amyloid precursor protein). APP can undergo cleavage down one of at least two pathways. In the first pathway, cleavage by the enzyme {alpha}-secretase prevents Aß formation, and instead produces the neuroprotective sAPP{alpha} fragment. However, if sequential cleavage by ß- and then {gamma}-secretases predominates, Aß is formed. This peptide can then aggregate over time to produce senile plaques, during which period it also evokes numerous neurotoxic effects (some of which may require a degree of oligomerization), or it can be degraded by enzymes such as neprilysin, insulin degrading enzyme or endothelin converting enzyme (Turner et al. 2004). Clearly, the net balance of production versus degradation and clearance will determine levels present in cerebrospinal fluid (CSF), which are low but nevertheless measurable even in individuals showing no signs of dementia whatsoever (Selkoe & Schenk, 2003). The presence of Aß in the CSF of non-demented individuals and in media from neuronal cell cultures (Tamaoka et al. 1997; Haass et al. 1992) indicates that, as well as having a potential pathological role in Alzheimer's disease, Aß has a role in the normal physiology of the central nervous system.


Figure 1
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  		Figure 1.  Cartoon depicting the proteolytic processing of amyloid precursor protein (APP) via non-amyloidogenic (left) and amyloidogenic (right) cleavage
Non-amyloidogenic cleavage occurs when {alpha}-secretase acts to liberate sAPP{alpha} and C83, the latter being cleaved by {gamma}-secretase to generate p3. Amyloidogenic cleavage by ß-secretase liberates sAPPß and the residual peptide is cleaved to produce C88 and Aß. Aß in turn can be degraded by enzymes including neprilysin, insulin degrading enzyme and endothelin cleaving enzyme (not shown).

 
The physiology of APP processing

The production and degradation of Aß has given us many insights into potential target processes for therapeutic intervention aimed at preventing Aß formation or accelerating its degradation. Certainly, numerous compounds have been designed to interfere with either the ß- or {gamma}-secretases, but progress has been hampered by the fact that these enzymes also cleave other substrate proteins, so it is not only the production of Aß that would be impaired (see reviews by Selkoe & Schenk, 2003; Vardy et al. 2005). Furthermore, although the potential for beneficial intervention remains great, it must be remembered that this proteolytic pathway is a physiological process – only when net Aß levels become excessive can this process be regarded as pathological. One major, and often overlooked, aspect of APP processing is that numerous peptides can be generated. These – and what is known of their roles – are summarized in Table 1. Clearly, there is much more to learn about the roles and activities of these peptides, but these are beyond the scope of this review. Instead, we will focus on the potential physiological roles of Aß. Such a discussion is complicated by the fact that many studies on the effects of Aß focus on the toxic actions of the peptide. Concentrations of Aß used in such studies are often far higher than levels found in CSF (1–10 nM). We have therefore directed our attention to studies where levels of applied Aß are in the < 100 nM range, or where endogenous Aß production/breakdown has been modified.


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  		Table 1. Cleavage products of amyloid precursor protein (APP) and their suggested physiological roles
 
Physiological control of synaptic activity

Several lines of evidence indicate that Aß may have a role in controlling synaptic activity. Kamenetz et al. (2003) found that evoked activity of hippocampal neurones in brain slices increased the production of Aß primarily by increasing trafficking of APP towards ß secretase sites at the cell membrane. This would promote Aß formation, but also increase production of other fragments (Fig. 1) such as AICD which may also modulate synaptic activity. At physiological expression levels of APP, this provided a negative feedback, since Aß depresses synaptic activity. Without such depression, synaptic activity could become excessive, leading to excitotoxicity. Indeed, {gamma} secretase inhibition led to increased EPSC frequency (Kamenetz et al. 2003), and kainate-induced seizures are potentiated in APP knockout mice (Steinbach et al. 1998). Further to these studies, a recent report indicated that specific stimulation of NMDA receptors up-regulated APP, inhibited {alpha}-secretase activity and promoted Aß production (Lesne et al. 2005). Collectively, these studies argue strongly that APP processing, and the presence of Aß itself, are closely associated with synaptic activity and may serve to provide physiological control of activity, guarding against excessive glutamate release.

What happens in the absence of Aß?

In primary cultures of central neurones inhibition of endogenous Aß production (by exposure to inhibitors either of ß- or {gamma}-secretases) or immunodepletion of Aß caused neuronal cell death (Plant et al. 2003). Importantly, this appeared neurone-specific, since a variety of non-neuronal cells were unaffected by the same treatments. Perhaps most important, however, was the fact that neuronal cell death in response to secretase inhibition could be restored by addition of physiological (picomolar) levels of Aß. The most common isoform, Aß(1–40), was most effective in this regard, and the commonly used fragment Aß(25–35), which retains many of the toxic properties of Aß, was almost completely ineffective (Plant et al. 2003). These findings provided compelling evidence for a role for Aß in neuronal survival. The underlying mechanism remains to be determined, but may involve altered expression of K+ channels. The activity of various K+ channel types has been implicated in neuronal survival or death, in part because they govern excitability and hence the excitotoxicity of released glutamate, but also because intracellular [K+] is a key determinant of apoptosis (Yu, 2003). Changes in K+ channel expression may also provide an explanation of the findings of Kamenetz et al. (2003). We recently reported that inactivating K+ currents of central neurones are suppressed in amplitude by inhibition of the production of endogenous Aß (Plant et al. 2005). As previously, this effect could be recovered by low levels of exogenous Aß. This therefore probably reflects a physiological role for Aß in controlling both excitability and cell survival.

We would predict from these findings that transgenic animals in which APP expression had been knocked out would show severe neurological deficits or lethality. This is not the case. APP-null mice show reduced branching of dendrites and fewer synaptic boutons but no reduction in neuronal number despite an absence of Aß (Dawson et al. 1999). Furthermore, these reported neurological changes may not be a result of a deficiency in Aß but of a deficiency in another product of APP processing or of APP itself. This is supported by the fact that an APP/APLP (amyloid precursor like protein) double knockout is lethal (von Koch et al. 1997). In addition, a transgenic knockout of ß-secretase in which levels of Aß are reduced to less than 10% of controls show no obvious deficits in either behaviour or neurology (Luo et al. 2001). On the other hand, one could argue that compensatory mechanisms in APP-null transgenic animals prevent toxic changes from occurring. One approach that would answer this would be to test the effects of an APP conditional knockout, but as far as we are aware these have yet to be made.

Hypoxia and APP processing

It has long been known that individuals who have suffered severe or chronic periods of hypoxia are more likely to develop Alzheimer's disease subsequently (Desmond et al. 2002). Indeed, hypoxic/ischaemic conditions up-regulate APP mRNA and protein (Hall et al. 1995; Kokmen et al. 1996; Jendroska et al. 1997; Shi et al. 2000), with consequent increases in Aß. In vitro, hypoxia increases Aß production (Taylor et al. 1999) with numerous consequences for cell function. Interestingly, many of these concern Ca2+ signalling (Smith et al. 2003, 2004), and disruption of Ca2+ signalling is a key event underlying neuronal death in Alzheimer's disease (LaFerla, 2002). One important aspect is the alteration of functional expression of ion channels: in cerebellar granule neurones, prolonged hypoxia leads to a selective up-regulation of L-type Ca2+ channels. This effect requires Aß formation, since it could be prevented by secretase inhibitors (Webster et al. 2006). This mechanism was explored further using a recombinant expression system: results (summarized as part of the cartoon of Fig. 2) indicated that hypoxia triggered increased Aß production. This effect was dependent on an increase of reactive oxygen species (ROS) derived specifically from mitochondria (this in itself is seemingly paradoxical, but continues to gain increasing support; see Guzy et al. 2005). Once formed, the Aß interacted directly with the recombinant L-type Ca2+ channel ({alpha}1C) subunit either to promote trafficking of channels towards, or inhibit retrieval of channels from, the plasma membrane. The net effect was increased Ca2+ channel protein at the cell membrane and hence increased Ca2+ conductance.


Figure 2
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  		Figure 2.  Synthesis, trafficking and retrieval of Ca2+ channels from the plasma membrane
Cartoon depicting the synthesis, trafficking and retrieval of Ca2+ channels from the plasma membrane under normoxia (upper picture). During sustained hypoxia, a rise of ROS from mitochondria triggers increased Aß formation which has multiple effects (see text for full description) including direct neuroprotection, increased transcription of protective factors such as vascular endothelial growth factor (VEGF) via stabilization of HIF, and altered trafficking of Ca2+ channels so that more are present and active in the plasma membrane.

 
The question arises, however, of whether this altered channel trafficking represents a physiological or pathological response of cells to hypoxia. On one hand, it is convenient to propose the idea of altered ion channel trafficking as a mechanism accounting for the clinical observations that prolonged hypoxia promotes development of Alzheimer's disease (see earlier). Alternatively, this can be regarded as a physiological process. This work – like the vast majority of in vitro cellular studies – was conducted using a ‘normoxic’ level of 150–160 mmHg (i.e. room air-equilibrated conditions). This is, of course, hyperoxic for any cell. For central neurones, this is a particularly high ambient level of O2. Central nervous system O2 levels vary, but rarely exceed approximately 40 mmHg (Li et al. 2005). Indeed, commonly, they can be half this value, as measured in animals breathing normal air (Grote et al. 1996). A compelling recent study has indicated that if neurones are isolated and maintained in primary culture at physiological O2 levels, they appear more robust, and can tolerate hypoxia to much greater levels than cells cultured at 20% O2 (Li et al. 2005). The protection appeared to derive in part from the production of VEGF (vascular endothelial growth factor), which in turn was driven by the stabilization of the {alpha}1 subunit of the transcriptional regulator, hypoxia inducible factor (HIF-1{alpha}). Indeed, pharmacological activation of HIF-1{alpha} promoted neuronal survival, as did exogenous VEGF (Li et al. 2005). But do these effects involve Aß in any way? At present we simply do not know, but available evidence points to a potentially exciting link. Soucek et al. (2003) examined the relationship between HIF-1, Aß and glucose metabolism in central neurones particularly with a view to examining potentially protective shifts in metabolic activity (generating greater reducing equivalents via glycolysis and the hexose monophosphate shunt). Crucially, they found that low levels of Aß could induce HIF-1 and thereby protect cells from the toxicity of exposure to high levels of Aß. In addition, activation of HIF also mimicked the protective effects of low levels of Aß. The authors themselves concluded that ‘an early function of Aß in ageing is neuroprotection’ (Soucek et al. 2003).

Summary

This brief review has highlighted some of an accumulating but diffuse collection of work pointing to important physiological roles for Aß. Given the presence of specific enzymatic pathways for the constitutive generation of Aß, coupled with the fact that there exist selective uptake, breakdown and clearance pathways for its removal, it seems inconceivable that Aß does not have a role to play in the normal function of the nervous system. Aß should not, therefore, be regarded merely as a toxic factor that requires eradication to avoid dementia. Clearly, there is evidence to suggest essential modulation of synaptic activity and neuronal survival, but what the full physiological extent of Aß activity (or indeed the activity of other products of APP proteolysis) remains to be seen.


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   Acknowledgements
 
Our work in this field has been/is supported by the MRC, the Wellcome Trust, The Alzheimer's Research Trust and the Alzheimer's Society.




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This Article
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