More than 20 million people worldwide have Alzheimer's disease, yet its causes remain mostly uncertain. Fresh findings provide molecular clues, linking this disease to another neurodegenerative disorder.
Investigations of the causes of Alzheimer's disease yield one culprit time and time again: abnormal build-up of amyloid-β (Aβ) peptides in the brain. Small, soluble aggregates of Aβ — Aβ oligomers — impair memory by disrupting memory-related functions of synaptic junctions between neurons1,2,3. But whether specific receptors mediate these adverse effects has remained unknown. In this issue, Laurén et al.4 (page 1128) show that the prion protein might mediate the pathogenic effects of Aβ oligomers.
The prion protein (PrP) is anchored to the cell membrane and associates with membrane microdomains called lipid rafts. It occurs in at least two conformational states. The cellular form, PrPC, is involved in maintaining the brain's white matter, and in regulating this tissue's innate immune cells, responses to oxidative stress and neuron formation5. The highly pathogenic form, PrPSc, is a misfolded version of PrPC and is resistant to enzymatic degradation. PrPSc is the main cause of a group of fatal neurodegenerative disorders called transmissible spongiform encephalopathies that includes Creutzfeldt–Jakob disease and mad cow disease6.
Aβ binds to and influences the function of many cellular proteins7. Laurén et al.4 therefore set out to identify proteins with greater affinity for Aβ oligomers than for freshly solubilized, putatively monomeric and non-toxic Aβ. Their unbiased genome-wide screen yielded PrP. Interaction between Aβ oligomers and PrP did not require the PrPSc conformation, although the authors did not explore whether PrPC misfolds into a PrPSc-like conformation on binding to Aβ oligomers.
Synaptic connections between neurons can be strengthened through a phenomenon called long-term potentiation (LTP), which provides a measure of synaptic plasticity related to learning and memory — two faculties that are compromised in Alzheimer's disease. To investigate what effect Aβ–PrPC interaction might have on LTP, Laurén et al. studied this process in slices of mouse hippocampus, a brain region crucial to learning and memory. They find that Aβ oligomers inhibit LTP in hippocampal slices from normal mice, but not in hippocampal slices from mice lacking PrPC. Similarly, LTP was not affected by Aβ oligomers in hippocampal slices from normal mice in which Aβ–PrPC interaction was blocked. So PrPC seems to be a main receptor for Aβ oligomers, mediating their deleterious effects on synaptic function.
The authors appropriately note, however, that they cannot exclude the existence of other receptors for Aβ oligomers, because PrP ablation reduced the binding of Aβ oligomers to neurons by only 50%. Alternative receptors might include the transmembrane proteins APLP1 and 30B, but, compared with PrPC, both of these showed much lower affinity and selectivity for Aβ oligomers4. Similarly, compared with PrPC, another Aβ-binding protein, RAGE, showed much lower affinity and selectivity for Aβ oligomers. However, earlier work indicated that disrupting Aβ–RAGE interaction inhibits programmed cell death in cortical neurons8 and prevents the induction of LTP deficits by Aβ oligomers in slices of entorhinal cortex9, another memory centre. Other potential receptors for Aβ oligomers have been proposed, but we are unaware of studies that rival the evidence Laurén and colleagues present4.
Laurén et al. find that, within PrPC, amino-acid residues 95–110 are crucial for Aβ binding. Interestingly, the enzyme α-secretase — which precludes Aβ production by cleaving the Aβ precursor protein APP within the Aβ domain — also cleaves PrPC between residues 111 and 112 (ref. 10), thus releasing from the membrane the portion of PrPC to which Aβ would otherwise bind. So one way to prevent both Aβ production and the activation of downstream mediators by PrPC might be to increase α-secretase activity.
Laurén and colleagues' observations create fertile ground for future investigations. One question is how the synthetic Aβ oligomers they characterized relate to the synthetic Aβ oligomers or natural, disease-associated oligomers that have been characterized by other researchers. For instance, does PrPC mediate the effects of Aβ dimers isolated from brains of people with Alzheimer's disease11, or of the Aβ*56 oligomer, which causes memory deficits in mouse models of this disease1,2?
How do the Aβ-induced effects on LTP that the authors observed in brain slices relate to cognitive impairments seen in Alzheimer's disease and in the related mouse models? To assess the clinical relevance and therapeutic potential of these findings4, interaction between PrPC and Aβ oligomers must be confirmed in patients with Alzheimer's disease, and the relationship between PrPC levels and cognitive decline should be explored. It would also be of interest to determine whether the cognitive deficits and behavioural alterations seen in mouse models of Alzheimer's disease can be prevented by ablating or reducing PrPC. For example, reducing the levels of the microtubule-associated protein Tau prevents cognitive deficits in mice with high levels of Aβ oligomers12. Human Tau forms complexes with PrP (ref. 13), so the toxicity of Aβ oligomers might involve interactions between PrPC and Tau.
And how exactly does the binding of Aβ to PrPC affect neuronal plasticity? Do Aβ oligomers block, enhance or distort PrPC functions? Do they exert their effects only on neurons or also on other brain cells such as microglia and astrocytes? Do they affect PrPC directly or do they block interactions between PrPC and a co-receptor (Fig. 1)? As Laurén et al. point out, the NMDA-type glutamate receptor interacts with PrPC, modulating its function. PrPC also activates a signalling cascade that regulates both NMDA receptors and Aβ-induced synaptic deficits14,15. Alternatively, PrPC may act as a 'Trojan horse', facilitating internalization of Aβ oligomers into vulnerable intracellular compartments (Fig. 1). Finally, PrPC might accelerate Aβ oligomerization outside the cell or change the Aβ folding landscape inside by acting as a 'pathological chaperone'. These possibilities are not mutually exclusive.
Notwithstanding these unresolved questions, the discovery that PrPC may be a mediator in the development of Alzheimer's disease is fascinating, not least from a therapeutic perspective. Drug development around this target should be facilitated by the already extensive knowledge of the cellular physiology of PrPC and by the fact that PrPC-deficient mice are viable and seem to have normal synaptic plasticity5.
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About this article
Molecular Neurobiology (2019)
Stability analysis of a steady state of a model describing Alzheimer’s disease and interactions with prion proteins
Journal of Mathematical Biology (2019)
Advanced Biosystems (2017)
Arquivos do Instituto Biológico (2017)
Molecular BioSystems (2016)