Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory

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Abstract

Amyloid-β precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-β (Aβ) peptide found in neuritic plaques of Alzheimer’s disease (AD) patients. Because shows neurotoxic properties, and because familial forms of AD promote Aβ accumulation, a massive international research effort has been aimed at understanding the mechanisms of Aβ generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPα (sAPPα), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Aβ appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Aβ, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Aβ, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease.

Introduction

Alois Alzheimer published in 1907 the first account of a neuropathological syndrome characterized by progressive dementia and deterioration of cognitive function (Alzheimer, 1907). Although age-related decay in mental function and memory loss were widely recognized at the time, Alzheimer was the first to demonstrate a relationship between specific cognitive changes, neurological lesions at autopsy, and clinical history. Two lesions in particular were described which now define Alzheimer’s disease (AD): dense fiber-like tangles, later termed neurofibrillary tangles, and darkly staining amyloid plaques that had previously been observed in other aged brain samples. It took a further 75 years before Allsop et al. (1983) identified biochemically the major constituent of these amyloid plaques as a 40–42 amino acid peptide termed amyloid-β (Aβ). Subsequent research determined that this peptide fragment originated from a larger precursor protein, named somewhat predictably, the amyloid-β precursor protein (AβPP, or APP as used here) (Kang et al., 1987). These advances led to the formulation of the amyloid hypothesis which states that overproduction of Aβ and its aggregation in senile plaques is the root cause of Alzheimer’s disease (Hardy and Allsop, 1991). The hypothesis received further support as genetic studies revealed that all cases of familial AD are linked to genes that affect the processing of Aβ from APP, namely, APP itself, presenilin-1 and presenilin-2 (Goate et al., 1991, Sherrington et al., 1996, Levy-Lahad et al., 1995). In addition to these highly penetrant mutations at least one other genetic polymorphism, in the gene for apolipoprotein E (ApoE), has been identified as a risk factor for developing AD and is thus believed to interact with APP and Aβ. The roles of Aβ in neurotoxicity and AD have been extensively reviewed (e.g. Selkoe, 1994, Howlett et al., 1995, Iversen et al., 1995, Forloni, 1996, Mattson, 1997).

Of course, no one hypothesis is resolute and demonstrating whether Aβ accumulation is a cause or effect of AD has proven extremely difficult. Indeed, neurofibrillary tangle formation correlates better with cognitive decline than amyloid plaque burden, raising questions about the significance of plaque amyloid (Wilcock and Esiri, 1982, Fischer et al., 1991). Thus, consideration has been given to Aβ deposition being merely a side effect of the disease process in which tangles play a primary role (Neve and Robakis, 1998). Neurofibrillary tangles are composed of hyperphosphorylated tau proteins which appear to play a role in microtubule function in normal brain (reviewed in Morishima-Kawashima and Ihara, 2002). Thus for the amyloid hypothesis to be correct, there should be a link between elevations in Aβ and the hyperphosphorylation of tau. This has been verified to some extent by the observation that APP transgenic mice, when crossed with mutant tau transgenic mice, yield offspring that develop significantly increased levels of neurofibrillary tangles (Lewis et al., 2001). Additionally, Aβ induces phosphorylation of tau in rat primary septal cultures in vitro (Zheng et al., 2002).

Aβ has remained a central feature of neurobiological research into AD through two significant refinements in the amyloid hypothesis. First, there has been a shift in emphasis away from the dense core amyloid to smaller aggregates, such as soluble oligomers and fibrils, as being major contributors to neural dysfunction. This is because it is now recognized that the level of soluble Aβ is raised in AD and correlated with the disease symptomatology (Lue et al., 1999, McLean et al., 1999). Furthermore, soluble Aβ exerts a number of physiological and cellular effects that may be sufficient to account for much of the cognitive decline, especially early in the course of AD. Second, now that the functions of APP and other fragments of this parent molecule are better understood, it has been proposed that changes in the activity of these fragments as a result of altered APP processing during the course of AD may also contribute to neuronal and thus cognitive dysfunction (Mattson, 1997, Mesulam, 2000). With these new developments has come a shift in the research toward understanding in more detail (1) the physiological actions of soluble Aβ, and (2) the normal functions performed by APP both in the brain and other organs, in order to more fully comprehend the disease process. In association with the resulting increased appreciation of the multiple roles played by APP and its fragments in neuronal cell biology, there has been a resurgence of interest in the amyloid hypothesis. This is reflected in the numerous recent reviews that touch on various aspects of APP processing and the activity of its fragments (Mattson, 1997, Furukawa, 1998, Russo et al., 1998, De Strooper and Annaert, 2000, Small et al., 2001).

The purpose of the present review is to summarize the current state of knowledge of APP and its fragments in normal cell biology and neural function, with a view to understanding their contributions to learning and memory. For APP and each of its major fragments, we discuss their synthesis, transport, localization and putative biochemical and molecular actions in neurons. We then review the effects of these fragments on synaptic transmission, plasticity, cellular excitability and signal transduction. These processes are fundamental to the mechanisms of memory storage in the brain, and therefore provide a framework for understanding the roles played by APP fragments in behavioral learning and memory. Collectively the evidence supports an hypothesis that APP fragments have competing disruptive and enhancing roles in neural function and memory processing, although normally the enhancing actions dominate. However when there is a shift towards the disease state, the likely combination of increased levels of disruptive fragments, such as Aβ, plus decreased levels of positively regulating fragments, such as sAPPα, results in the development of synaptic and cellular impairments that underpin major deficits in memory and other cognitive functions.

Section snippets

Roles of full-length APP in normal neuronal function

APP is a resource-rich molecule. It has at least three isoforms arising from the alternative splicing of its pre-mRNA, it is extensively processed post-translationally by both glycosylation and specific proteolytic cleavage, and the resulting fragments seem to participate widely in adhesion, neurotrophic and neuroproliferative activity, intercellular communication and membrane-to-nucleus signaling. APP is not limited to the brain but is almost ubiquitous throughout the body, with different

Proteolytic processing of APP

The neuron specific-isoform APP695 is bound to the membrane with classic features of an orphan receptor (ligand yet to be identified; see Section 2.2.1). Unlike most receptors, however, it is sensitive to proteolytic cleavage, with a complex processing pathway that results in secretion of relatively large fragments of ∼600 amino acids that are derived from the extracellular amino-terminal domain and, depending on the cleavage pattern, smaller fragments including Aβ as well as various C-terminal

Regulation of secreted APP release

The release of sAPP (α and β) occurs constitutively, but it is also regulated by neural activity and can be influenced by agonists of various neurotransmitter receptors. For example, application of agonists of the type one metabotropic glutamate (mGlu1) receptor to cultured HEK293 cells expressing the receptors increases sAPP release (Nitsch et al., 1997). Similarly, carbachol activation of m1 and m3 muscarinic acetylcholine (mACh) receptor subtypes increases the release of sAPP from HEK293

Roles of amyloid-β in neuronal function

The Aβ peptide that arises from β and γ-secretase processing of APP has received much attention as a major player in Alzheimer’s disease. There is no disputing that Aβ is toxic to cultured cells of various types (reviewed in Walsh et al., 2002b) and also has long-term damaging effects when injected directly into the brain (McKee et al., 1998). However, Aβ is found in a variety of forms and association states and it is not easy to quantitate these individual forms in vivo. Furthermore, Aβ is

Carboxy-terminal binding proteins

Apart from sAPP and Aβ, the APP fragments that have received the most attention in terms of their cellular and molecular functions are the intracellular carboxytermical fragments (CTFs). Although the intracellular tail of APP may couple to Go proteins, as reviewed in Section 2.2.1, it also binds many other proteins. To complicate matters further, most seem to be adapter proteins which in turn bind other components to exert their effects. Thus, regulation of the functional effects of the APP

Summary and conclusions

The molecular causes of AD are complex and still poorly understood. Much has been gleaned from cases of FAD, but these make up only a small percentage of the total AD population. Although all these cases point to altered APP processing as a major component in the disease pathogenesis, establishing the downstream effects of altered APP processing has been a slow and laborious process. Through a massive research effort over the last two decades, it has now become clear that APP and its fragments

Acknowledgements

We thank Ms. Chanel Taylor for proofreading of an earlier version of the manuscript. Preparation of this review was supported by grants from the New Zealand Neurological Foundation, the Otago Medical Research Foundation, the New Zealand Lottery Grants Board, and the Health Research Council of New Zealand.

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      Citation Excerpt :

      APP is an integral membrane protein expressed in various tissues. It is involved in iron export [110], neural plasticity [111], regulation of synapse formation [112], and also possesses antimicrobial activity [113]. However, sequential APP cleavages give rise to a peptide called β-amyloid (Aβ), which aggregates to form senile plaques in Alzheimer's disease (AD) brain [114] .

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