Prion protein in Alzheimer‘s disease

Figure 1. Protective role for PrP^C in Alzheimer‘s disease.

With the rise in life expectancy, Alzheimer‘s disease (AD) has become of increasingly significant concern to healthcare professionals and the population as a whole. As the most prevalent mental health issue affecting our aging population, with over 24 million sufferers worldwide and an estimated cost that runs into billions of dollars [101], scientific interest remains prioritized on novel therapeutic strategies. Currently, there remains no adequate treatment to cure or prevent disease progression and only limited options to alleviate some of the symptoms [1]. AD is characterized pathologically by extracellular senile plaques and intracellular neurofibrillary tangles. The major component of the senile plaque is the amyloid β (Aβ) peptide, which is derived from the proteolysis of the large transmembrane amyloid precursor protein (APP). Cleavage of APP by β-secretase (β-site APP-cleaving enzyme [BACE]1) is the first step in releasing neurotoxic Aβ peptides; Aβ_1-40 is the most prevalent form, whilst Aβ_1-42 is more fibrillogenic and is the major species found in the senile plaques [2]. Rapid advances are being made to further understand the pathological development of AD, particularly relating to the roles of cellular proteins in the production, aggregation and metabolism of Aβ [1].

The prion protein (PrP) is the causative agent of the transmissible spongiform encephalopathies (TSEs), which include scrapie in sheep, bovine spongiform encephalopathy or ‘mad cow disease‘ in cattle and Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker disease and fatal familial insomnia in humans [3]. In TSEs, the normal cellular isoform of PrP (PrP^C) undergoes a post-translational conformational change to create the infectious, disease-causing isoform PrP^Sc[4]. Whilst being an absolute prerequisite for disease propagation by providing the substrate for conversion, a precise physiological role for PrP^C remains uncertain, especially as knockout mice in which the gene encoding PrP has been ablated are without gross anatomical defect or overt pathology. However, growing evidence indicates that PrP^C may have a role in neuronal defence against oxidative stress, either by direct chelation of redox-active metal, as a sacrificial molecule or as a copper-sensitive stress sensor [4].

Here, we summarize recent data demonstrating a direct role for PrP^C in regulating the production of the Aβ peptide and, potentially, the progression of AD. As oxidative stress is an early event in the pathogenesis of AD and as PrP^C can protect cells against oxidative stress, we highlight this link, and speculate whether molecules capable of mimicking the antiamyloidogenic and antioxidative functions of PrP^C may provide a novel approach in the treatment of AD.

Protective role for PrP^C in Alzheimer‘s disease

Recently, we reported that increasing the amount of PrP^C within neuronal cells dramatically inhibited the formation of both Aβ_1-40 and Aβ_1-42[5]. Conversely, reducing the amount of PrP^C in cultured neuronal cells through the use of small interfering RNAs resulted in an increase in Aβ production, while the brains from PrP-knockout mice had increased Aβ levels compared with mice with normal amounts of PrP^C[5].

Together, these observations indicate that PrP^C has a role in regulating the production of the neurotoxic Aβ peptide and, hence, protecting against AD (Figure 1). Further analyses of the metabolism of APP revealed that PrP^C was regulating the production of Aβ at the first step in the proteolytic processing of APP, which is carried out by BACE1. However, PrP^C did not alter the amount of BACE1 in the cells nor did it directly inhibit its catalytic activity towards a short synthetic peptide substrate. Coimmunoprecipitation studies indicated that PrP^C interacted directly with BACE1, and the use of mutants of PrP^C revealed that this interaction was glycosaminoglycan-dependent and required PrP^C to be localized in cholesterol-rich domains of the cell membrane [5]. Further investigation of the mechanism by which PrP^C inhibits the cleavage of APP by BACE1 may provide the opportunity for the design of novel PrP^C agonists that mimic this effect and that would have therapeutic potential for AD.

This novel role for PrP^C in inhibiting the cleavage of APP by BACE1, thereby regulating the production of the neurotoxic Aβ peptide (Figure 1), raises the possibility that a small reduction in the level of functional PrP^C in individuals may increase the amyloidogenic processing of APP in a subtle way over decades to affect long-term Aβ production, which in turn could accelerate the deposition of amyloid in the brain and the onset of AD. Further studies are required to address this hypothesis. However, if true, one would predict that complete absence of PrP^C in humans would lead to the onset of AD at a relatively early age as there would be no PrP^C to regulate the BACE1 cleavage of APP, with the result that the production of Aβ would be higher throughout life. Support for this hypothesis comes from two familial prion diseases that are due to mutations (Y145^stop and Q160^stop) in PrP^C, which result in truncated proteins that are rapidly metabolized by the cell [6,7]. In both cases, the onset of clinical disease occurred in the fourth decade of life and, in the Y145^stop case, a diagnosis of AD was initially made [6]. Thus, these natural mutations in PrP^C provide compelling evidence that the loss of functional PrP^C in humans may lead to the early onset of AD.

Oxidative stress in Alzheimer‘s disease

In addition to the direct effect of PrP^C on the production of Aβ outlined above, it is also important to consider that AD is a disease of aging, a phenomena associated with an increase in reactive oxygen species (ROS) [8]. Oxidative stress occurs when the rate at which a cell produces ROS is outweighed by the inherent ability of the cell to quench them. A substantial body of evidence exists to demonstrate that oxidative stress is an early event in the pathogenesis of AD (Figure 1) and is present even before the hallmark features of AD are detectable [9].

Oxidative modification in susceptible neurons of AD has been found in almost all classes of cellular macromolecules, and includes DNA-strand breaks and fragmentation, protein nitration and carbonyl formation and lipid peroxidation [10,11]. Interestingly, oxidative damage decreases with disease progression, such that markers that were elevated during the earlier stages of disease decrease as the disease progresses [12]. This would indicate that while ROS not only cause damage to the cellular infrastructure, they may also provoke physiological responses, such as complementary upregulation of antioxidant defences [12]. Furthermore, the deposition of Aβ may be an attempt at functional adaptation to the pro-oxidative environment [13,14]. The chelation of redox-active metals within senile plaques and intraneuronal inclusions, along with the demonstration that the neurons containing such inclusions are protected from cell death, indicate that Aβ deposition may have a beneficial effect.

As ROS-mediated damage appears to be a key factor in AD pathogenesis, measures to reduce the oxidant burden within the cell could contribute towards reducing disease etiology. A growing body of evidence indicates a role for PrP^C in the protection of neuronal cells against oxidative stress [15]. PrP^C appears to provide crucial early detection of ROS in the local environment by undergoing cleavage following exposure to radical species [16]. Cells in which this cleavage of PrP^C occurred were able to cope better under oxidative stress.

However, if the protein was unable to undergo cleavage, for example owing to disease-associated mutation, the cells remained compromised [16]. This substantiates a normal physiological function for PrP^C in upregulating the antioxidant defence of neuronal cells. Interestingly, the expression level of PrP^C increases with age [17], suggesting that a physiological mechanism may be in place to reduce the consequence of age-related adventitious ROS production. Furthermore, aging mice showed impairment of both short- and long-term memory retention when there was an absence of PrP^C[18].

Conclusion

Taken together, these data suggest that the beneficial effect of PrP^C may be at least twofold; as a direct cellular inhibitor of the amyloidogenic processing of APP to produce the neurotoxic Aβ and as a key component of the cellular protection against oxidative stress. As both Aβ and oxidative stress are intimately associated with the development and progression of AD, then it follows that PrP^C may have a fundamental role to play in protecting against this devastating neurodegenerative disease. In the future, the identification of molecules able to mimic or recapitulate these antiamyloidogenic and antioxidative functions of PrP^C may provide a new avenue for the development of AD therapeutics.

Future perspective

The discovery of a role for PrP^C in regulating the production of the neurotoxic Aβ peptide, and thus in directly protecting against AD, as well as its antioxidant role, opens up new avenues for research in coming years. As we learn more about the mechanisms underlying both of these cellular roles of PrP^C, it may be possible within 5–10 years to identify and/or develop small molecules that mimic these protective functions. Further ahead, such novel therapeutics could be used alongside drugs already in development and in clinical trials in our battle against the most prevalent and devastating neurodegenerative disease of old age.

Executive summary

Introduction

• Alzheimer‘s disease (AD) is the major neurodegenerative disease of old age for which there is currently no cure.

• AD is characterized by the build up of the neurotoxic amyloid-β (Aβ) peptide, which is deposited in senile plaques in the brain.

• Cellular prion protein (PrP^C), which causes the transmissible spongiform encephalopathies, is involved in the protection of neurons against oxidative damage.

Protective role for the prion protein in Alzheimer‘s disease

• In neuronal cells PrP^C dramatically inhibits the formation of Aβ through inhibiting the action of the β-secretase β-site amyloid precursor protein-cleaving enzyme 1.

• In mice lacking PrP^C, the amount of Aβ in the brain is increased, while in humans with mutations in PrP^C that lead to lack of functional protein an early diagnosis of AD was made.

Oxidative stress in Alzheimer‘s disease

• Aging is associated with an increase in reactive oxygen species and oxidative stress is an early event in the pathogenesis of AD.

• PrP^C protects cells against oxidative stress and the level of PrP^C in the brain increases with age.

Conclusions

• PrP^C has beneficial effects, as a direct inhibitor of the production of Aβ and in the protection against the oxidative environment known to promote AD progression.

• Identification of molecules able to mimic or recapitulate the beneficial functions of PrP^C may provide a new avenue for AD therapeutics.

Future perspective

• Such therapeutics could be used alongside drugs already in development and in clinical trials in our battle against the most prevalent and devastating neurodegenerative disease of old age.

Financial & competing interests disclosure

We thank the Medical Research Council of Great Britain for financial support of our work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.