Review
Mechanisms of Aβ mediated neurodegeneration in Alzheimer's disease

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Abstract

Development of a comprehensive therapeutic treatment for the neurodegenerative Alzheimer's disease (AD) is limited by our understanding of the underlying biochemical mechanisms that drive neuronal failure. Numerous dysfunctional mechanisms have been described in AD, ranging from protein aggregation and oxidative stress to biometal dyshomeostasis and mitochondrial failure. In this review we discuss the critical role of amyloid-β (Aβ) in some of these potential mechanisms of neurodegeneration. The 39–43 amino acid Aβ peptide has attracted intense research focus since it was identified as a major constituent of the amyloid deposits that characterise the AD brain, and it is now widely recognised as central to the development of AD. Familial forms of AD involve mutations that lead directly to altered Aβ production from the amyloid-β A4 precursor protein, and the degree of AD severity correlates with specific pools of Aβ within the brain. Aβ contributes directly to oxidative stress, mitochondrial dysfunction, impaired synaptic transmission, the disruption of membrane integrity, and impaired axonal transport. Further study of the mechanisms of Aβ mediated neurodegeneration will considerably improve our understanding of AD, and may provide fundamental insights needed for the development of more effective therapeutic strategies.

Introduction

Central to most current Alzheimer's disease (AD) research is a small 39–43 amino acid peptide known as amyloid-β (Aβ). Aβ is an amyloidogenic cleavage product of the Aβ A4 precursor protein (APP), an 87 kDa transmembrane protein with apparent homology to a cell-surface receptor (Kang et al., 1987). Several metalloproteinases (secretases) are known to cleave APP, with α-secretase mediating an APP processing pathway often regarded as normal since this pathway is not directly implicated in the development of AD. Alternate APP processing by the combined activity of γ- and β-secretases gives rise to the Aβ peptide (Fig. 1). APP is ubiquitously expressed, and cells possess the enzymatic machinery required not only to produce Aβ but also to degrade it, suggesting that the production of Aβ from APP may serve a normal biological role. The non-pathological role for Aβ is yet to be established, but several reports have indicated the involvement of Aβ/APP in a broad range of cellular processes (Table 1).

The post-mortem AD brain is defined histopathologically by the presence of amyloid deposits in affected areas of the brain. Following its purification from cerebrovascular amyloid deposits and the extracellular amyloid plaques that characterise the AD brain (Glenner and Wong, 1984a, Glenner and Wong, 1984b; Masters et al., 1985; Selkoe, Abraham, Podlisny, & Duffy, 1986), considerable research attention turned towards attempting to elucidate the neurotoxic mechanisms of Aβ. Aβ is now widely regarded as central to the development of AD, with the Aβ amyloid pathway an important underlying factor that determines the peptide's toxicity. Developing therapeutic strategies that aim to inhibit the Aβ amyloid pathway is therefore an area of intense research focus (Masters & Beyreuther, 2006).

Evidence for the relationship between the development of AD and abnormal Aβ production comes from the familial forms of AD. Familial AD (fAD) only accounts for ∼10% of all AD cases, but the most significant fAD mutations are all associated with APP processing to yield Aβ. Mutations within APP that are adjacent to the α-, γ- and β-secretase cleavage sites have been identified (Chartier-Harlin et al., 1991, Citron et al., 1992, Games et al., 1995, Goate et al., 1991), and by altering secretase activity at these sites the relative Aβ yield from APP is affected. Familial APP mutations increase the relative production of Aβ42 compared to Aβ40 (Suzuki et al., 1994), and this may be an important factor in the development of AD since Aβ42 tends to be more toxic and more amyloidogenic. Familial AD mutations are also associated with components of the APP secretases, such as presenilin 1 from γ-secretase. It is less clear however whether these fAD mutations increase Aβ production or the ratio of Aβ42 compared to Aβ40 (Shioi et al., 2007).

Due to their abundance within amyloid deposits, insoluble high molecular weight Aβ fibrils were initially believed to be the primary toxic form of Aβ. However, focus shifted onto soluble low molecular weight forms after studies indicated that the abundance of these Aβ species within the AD brain appeared to correlate best with AD severity. McLean et al. (1999) for example prepared phosphate buffered saline extracts from AD brain sections and demonstrated that abundance of Aβ species in the non-sedimentable fraction (including Aβ monomers, dimers and trimers) correlated best with markers of disease severity such as density of neurofibrillary tangles and age at death. Numerous in vitro and in vivo studies now show that Aβ species soluble in diverse solvents and media solutions are substantially more potent than insoluble Aβ (Crouch et al., 2005, Hartley et al., 1999, Lambert et al., 1998, Lambert et al., 2001, Walsh et al., 1999). Such studies therefore provide increasing evidence that Aβ mediated neurodegeneration in AD is the result of toxic pools of soluble Aβ, and that the large, extracellular aggregates of insoluble Aβ merely represent end-stage products of the disease.

In the 20 years since Aβ was identified as an important constituent of the amyloid deposits that characterise the AD brain, this small peptide has received intense research focus as an important factor that contributes directly to development of the disease. Relative abundance of the peptide within the AD brain is central to disease development, but less certain are the mechanisms of Aβ mediated neurotoxicity. Several potential mechanisms have been proposed, and in this review we discuss just some of the data to indicate a direct role for Aβ in the neurodegeneration of AD. These mechanisms are summarised in Fig. 2. Our focus in this review is to present some of the mechanisms of Aβ toxicity reported over recent years, but we first describe two important events that underlie all Aβ toxicity; Aβ oligomerisation and Aβ accumulation.

Section snippets

Aβ oligomerisation and the toxic Aβ species

Central to the Aβ hypothesis of AD is that disease progression is the result of an increased Aβ burden in affected areas of the brain. Equally important to total Aβ load however is the aggregation state in which Aβ is present. Initially produced as a soluble 4 kDa peptide, the amyloidogenic Aβ readily interacts with other Aβ molecules to progressively form a wide range of oligomers and soluble aggregates. Continued amyloidogenesis ultimately gives rise to the high molecular weight insoluble Aβ

Aβ turnover and accumulation in AD

Critical in AD is the accumulation of Aβ within affected areas of the brain, and developing therapeutic strategies that aim to decrease Aβ load is an important area of AD research. Some fAD data indicates that Aβ accumulation may be the result of increased Aβ production and/or stabilisation, but less certain is whether Aβ accumulation may be due to decreased Aβ degradation or perhaps decreased Aβ clearance from the brain. Genetic evidence for this possibility is yet to be produced, but it may

Potential mechanisms of Aβ mediated neurodegeneration

Regardless of the biochemical or genetic factors that determine Aβ accumulation and/or oligomerisation, it is now widely recognised that Aβ has the potential to contribute directly to the cognitive decline and neurodegeneration that is characteristic of AD. The remaining sections of this review presents research into just some of the potential mechanisms of Aβ mediated neurodegeneration.

Conclusion

The development of effective therapeutic strategies for treating any disease condition requires an understanding of the underlying biological mechanisms involved. In the case of AD there is overwhelming consensus that an aberrant accumulation of Aβ within affected areas of the brain contributes directly to development of the disease. Research into the mechanisms of Aβ mediated neurodegeneration over the past 20 years has revealed that Aβ is central to dysfunctional processes as diverse as

Acknowledgements

The authors thank Ms Gulay Filiz for her assistance in preparing the manuscript.

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    These authors contributed equally to the work.

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