Pathogenic Aβ generation in familial Alzheimer’s disease: novel mechanistic insights and therapeutic implications
Introduction
Protein deposits in the brain of affected patients appearing over time as neuritic plaques composed of aggregated amyloid β-peptide (Aβ) species and neurofibrillary tangles composed of hyperphosphorylated tau are the major pathological hallmarks of Alzheimer’s disease (AD), the most common form of dementia worldwide [1,2]. According to the amyloid cascade hypothesis, Aβ is believed to trigger the disease, which ultimately causes neuronal cell death through a poorly understood pathway involving tau aggregation [3]. Aβ is generated from a larger type I membrane protein, the β-amyloid precursor protein (APP), through sequential cleavages by the membrane-embedded aspartyl proteases β-secretase and γ-secretase, the latter being a multi-component complex, which contains presenilin 1 (PS1) or 2 (PS2) as the catalytic subunit [4]. The amyloid cascade hypothesis is strongly supported by the identification of mutations in APP, PS1 and PS2 in familial AD (FAD) cases. Most FAD mutations affect the cleavage by γ-secretase and cause relative increases in the production of the longer, highly aggregation-prone and neurotoxic 42 amino acid Aβ (Aβ42) variant over the major form Aβ40 [5]. Recently, FAD mutations have also been identified which cause aberrant levels of the slightly longer pathogenic Aβ43 species, which is normally produced only in tiny, much lower amounts than Aβ42 [6, 7, 8, 9]. FAD mutations in PS1, which contains the vast majority of the mutations, and PS2, are spread all over the molecule while in APP, these mutations are located in the transmembrane domain (TMD) within and around the γ-secretase cleavage site domain [4]. Additional APP mutations located in the extracellular Aβ region and at the β-secretase cleavage site affect aggregation properties of Aβ or strongly increase the production of total Aβ, respectively [5]. Interestingly, in further support of the amyloid hypothesis, a protective Aβ-lowering mutation lying in immediate vicinity to the β-secretase cleavage site has been identified in the Icelandic population [10]. While Aβ species are normally secreted into the extracellular space, a large intracellular pool of Aβ42, which could play an important role in disease pathogenesis, has recently been shown to be generated by PS2, which is predominantly located in late endosomal/lysosomal compartments [11].
Although the effects of FAD mutations on Aβ ratios are known since more than two decades, the underlying mechanisms have only recently become clear. Here we will review the major progress made in the past few years by advanced biochemical approaches and exciting breakthroughs in the structural biology of γ-secretase that can now explain how these mutations cause pathological increases in the generation of longer Aβ42/43 species. In addition, we will describe the recently made novel insights into mechanism and functional properties of γ-secretase modulators (GSMs), drugs that lower Aβ42/43 levels by enhancing the production of shorter Aβ37/38 species. Finally, we provide a perspective of how these insights on the mechanism of FAD mutants and the action of GSMs could be brought together for advanced clinical trials to treat AD, for which there is still no cure available.
Section snippets
Mechanistic and structural insights into pathogenic Aβ generation
The various Aβ species are generated by γ-secretase cleavage of the C99 APP-C-terminal fragment (CTF) in a stepwise manner [12,13] (Figure 1a). Through an initial ε-cleavage at the ε48/49 sites, Aβ48/49 and the corresponding APP intracellular domains (AICD) are generated. By multiple additional γ-secretase cleavages, which release tri- and tetrapeptides as byproducts, the C-terminus of Aβ is sequentially trimmed to shorter Aβ products. The finally generated Aβ37-43 species are short enough to
Lowering Aβ42/43 by modulation of γ-secretase activity
In contrast to classical γ-secretase inhibitors (GSIs), GSMs maintain the initial cleavage of γ-secretase substrates thereby avoiding inhibition-caused side effects such as that of Notch1 cleavage inhibition [27]. There are two major classes of GSMs, acidic and non-acidic, bridged-aromatic GSMs [28]. Acidic GSMs such as GSM-1 [29] are based on non-steroidal anti-inflammatory drugs (NSAIDs) like sulindac sulfide and ibuprofen, which were the first reported class of GSMs [30]. They modulate the
Implications for clinical trials
Despite the key role of Aβ in the etiology of AD, clinical trials have only very recently shown that drugs targeting Aβ can have measurable clinical efficacy. After a long frustrating period of failed trials, which also increasingly questioned the validity of Aβ as target, new hope that it is indeed the key target molecule for disease modification comes from one of two phase 3 studies with aducanumab, a promising antibody for Aβ-directed immunotherapy approaches [67]. Although the aducanumab
Conclusions
The past few years have provided major breakthroughs in our understanding of the mechanisms underlying pathogenic Aβ42 and Aβ43 species. We have learned that changes in the processivity are caused by several mechanisms that include changes in the stability of Aβ–γ-secretase complexes as well as altered C99 substrate positioning and fitting into subsites and Aβ pathway selection. The first structure of γ-secretase in complex with APP and Notch1 substrates provide important starting points for
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by the Deutsche ForschungsgemeinschaftFOR2990 (H.S). We thank Dr. Johannes Levin for helpful comments on the manuscript.
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