Prion Protein and Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent form of dementia with large impact on population over the age of 65 years [1]. The most distinctive symptomatic phase during the disease is the decline of the cognition with the loss of synapses [2-5]. In recent years, there is debate on cellular form of PrP (PrPC) and its role in AD as a negative key player or protective modulator in-conjugation with amyloid-β oligomers (AβOs) [6-9]. A recent report published in The Journal of Neuroscience showed the effect of PrPC ablation during the advanced stages of AD [10]. The mice study also demonstrated the onset of pathology and the role of PrPC during the disease progression without disrupting any interlinked pathways. Interestingly, the interaction between PrPC and AβOs appears to be involved in maintaining cognitive impairment in later stages of AD, making it an attractive therapeutic target [10,11].

The mainstream effort in explicating the role of PrPC in AβO-induced synaptic dysfunction is less controversial. Recent reports on AβO-induced pathology emphasizes on the hypothesis that PrPC acts as the major influential receptor, and admitting the presence of other associative risk modulators. Kostylev and colleagues used a PrPC-ELISA (PLISA) to quantify the AβO-PrPC interaction in brain tissue from several mouse models of AD and also healthy and AD human brain [12-14]. This study found that PrPC interacting AβOs are highly correlated with learning and memory deficits in multiple mouse models of AD as defined by PLISA activity [14]. Furthermore, PLISA activity disappeared with PrPC mediated depletion of high-molecular weight AβOs from mouse of the varying mouse models. In multiple mouse models of AD, a high-molecular weight AβO species demonstrated to be responsible for the deficits in learning and memory. While there exists some conflicting evidence, a large body of genetic and biochemical evidence suggest PrPC is the associated receptor for AβO-dependent synaptic deficits.

Our recent research outcomes also demonstrated the interacting proteins of prion protein to elucidate the selective domains capability in slowly and rapidly progressive forms of AD [15] and PrPC influence on Aβ and 3PO-tau processing [16]. Although AβOs may lead to memory failure through multiple mechanisms [17], their interactions with PrPC have been shown to mediate aberrant signaling pathways, synapse loss, and cognitive decline in AD models [10]. Binding of AβOs to PrPC recruits Type 5 metabotropic glutamate receptors (mGluR5) to abnormally activate Fyn kinase and impair synapse function [13,18]. These results have elevated the significant demand of whether interfering with AβO-PrPC interactions could mitigate AD phenotypes and rescue memory. Interestingly, endogenous or synthetic ligands of PrPC interrupt AβO-mediated signaling and prevent neurotoxicity in neurons [19,20]. Nonetheless, therapeutic implications and detailed mechanisms linking PrPC to AD progression still remain to be determined.

The interactive association of Aβ modulates the physiological role of many cellular proteins [21]. Many reports demonstrated that the AβOs and PrPC interactions did not necessitate the scrapie form of PrP (PrPSc) conformation and showed 50% reduction of binding of AβOs to neurons after PrP ablation [22]. However, we cannot ignore the presence of other receptors for AβOs. APLP1, 30B, and RAGE emanates with alternative receptors for AβOs but with much lower affinity and selectivity for AβOs [22,23]. Laurén et al. discover that the amino-acid residues 95–110 of PrPC are critical site for Aβ binding [23]. Interestingly, the enzyme α-secretase—which precludes Aβ production by cleaving the Aβ protein precursor within the Aβ domain—also cleaves PrPC between residues 111 and 112 [24], thus releasing from the membrane the portion of PrPC to which Aβ would otherwise bind. So one way might be the increase of α-secretase activity, to prevent both Aβ production and the activation of downstream mediators by PrPC.

The emerging research outcome and involvement of PrPC drives new queries: How precisely is neuronal plasticity affected by the interaction of Aβ to PrPC? Do AβOs block, increase, or modify PrPC functions? How do these interactive associations between PrP and AβOs employ their effects on neurons and other brain cells such as microglia and astrocytes? Lastly, how can these associations be utilized for clinical relevance and therapeutic potential in AD?

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[3] Arendt T (2009) Synaptic degeneration in Alzheimer's disease. Acta Neuropathol 118, 167-179.
[4] Nimmrich V, Ebert U (2009) Is Alzheimer's disease a result of presynaptic failure? Synaptic dysfunctions induced by oligomeric beta-amyloid. Rev Neurosci 20, 1-12.
[5] Marcello E, Epis R, Saraceno C, di LM (2012) Synaptic dysfunction in Alzheimer's disease. Adv Exp Med Biol 970, 573-601.
[6] Schwarze-Eicker K, Keyvani K, Gortz N, Westaway D, Sachser N, Paulus W (2005) Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging 26, 1177-1182.
[7] Peretti D (2010) Is PrPC a mediator of Aβ toxicity in Alzheimer's disease? J Neurosci 30, 11883-11884.
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[10] Lima-Filho RAS, Oliveira MM (2018) A role for cellular prion protein in late-onset Alzheimer's disease: evidence from preclinical studies. J Neurosci 38, 2146-2148.
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Last comment on 26 December 2018 by Claudio Russo, PhD


Zafar’s blog discussing the involvement of prion protein in Alzheimer’s disease (AD) is pertinent after pioneering descriptions of PrPC co-localization with β-amyloid in amyloid plaques in AD [1].

Although those preliminary studies suggested that β-amyloid was likely not bound to PrP, subsequent studies have identified fine interactions of these proteins which have implications in the pathogenesis of the disease. Moreover, interactions of PrPC are not limited to β-amyloid but interactions also implicate other proteins as α-synuclein and tau.

Several membrane receptors can bind to oligomeric β-amyloid (Aβo). Among these receptors, PrPC interacts with Aβo neurotoxic species; the N-terminal residues 23-27 and the CC2 region (amino acids 94-110) of PrPC are relevant for PrPC interactions with Aβo, as the removal of any of these regions results in a reduction of PrPC/Aβo binding. In addition, the C-terminal domain (aa 120-144) of PrPC participates in Aβ fibril formation. In parallel, binding Aβo to PrPC also triggers an increase in tau phosphorylation.

PrPC is also a binding partner of α-synuclein and modulates α-synuclein neuronal spreading: the absence of PrPC decreases α-synuclein spreading in vivo, whereas PrPC over-expression enhances α-synuclein spreading and α-synuclein phosphorylation. Aβo and α-synuclein share the CC2 domain of PrPC as a binding domain [2].

Strong interplay among α-synuclein, tau and Aβ may synergistically promote shared seeding. The identification of PrPC as a receptor for Aβo and α-synuclein opens new avenues for drug discovery.

[1] Ferrer I, Blanco R, Carmona M, Puig B, Ribera R, Rey MJ, Ribalta T (2001) Prion protein expression in senile plaques in Alzheimer's disease. Acta Neuropathol 101, 49-56.
[2] del Río JA, Ferrer I, Gavín R (2018) Role of cellular prion protein in interneuronal amyloid transmission. Progr Neurobiol 165-167, 87-102.

Zafar’s comments and the final questions she made regarding the interplay between Αβ and PrP are central in both AD and prion diseases. Recent research demonstrated that amyloid and prion can interact each other: however it is still unclear whether oligomeric Aβ (OAβ) influences PrP activity or, vice versa, PrP modulates Aβ aggregation and toxicity… or both. The concept of Aβ “strains” and their role in AD phenotypes is still undercover[1], and the PrP role in Aβ “strain” modulation is a relatively new and still unwritten history. 

Alzheimer’s, compared to Prion, even considering its intrinsic variability, is a very different disease whose overall picture must necessarily consider some characters that are related to each other: presenilins, apolipoprotein E and AβPP. How PrP can be fitted in this framework is still controversial. It is interesting, from this point of view, the recent report by Pagano K. Et al., [2] in which they show that PrP is able to differently interact with the forming Aβ oligomers, even with the highly toxic pyroglutamate-modified N-truncated isoform, driving their internalisation and toxicity. Besides, if OAβ induce neurotoxicity and Tau aggregation, why Aβ-based therapies failed? The elephant in the room in the AD field resides in the unclear pathological relationship between Aβ and Tau: how Aβ influences or induces Tau aggregation? Many hypothesis, but few certainty. There is a PrP effect on this? Is maybe PrP the link between Aβ and Tau? Although it is tempting to run on the easy road considering OAβ the direct target of PrP, it is rather more likely that the involvement of PrP in vesicles recycling and cell-signalling events would represent a more suitable path that group also the above mentioned characters of this abnormally intricate history [3,4]. 



[1] Tabaton M, Gambetti P. (2006) Soluble amyloid-beta in the brain: the scarlet pimpernel. J Alzheimers Dis 9(3 Suppl), 127-32

[2] Pagano K, Galante D, D'Arrigo C, Corsaro A, Nizzari M, Florio T, Molinari H, Tomaselli S, Ragona L. (2018) Effects of Prion protein on Aβ42 and pyroglutamate-modified AβpΕ3-42 oligomerization and toxicity. Mol Neurobiol Jul 6.[Epub ahead of print]

[3] Zafar S, Shafiq M, Younas N, Schmitz M, Ferrer I, Zerr I (2017) Prion protein interactome: identifying novel targets in slowly and rapidly progressive forms of Alzheimer's disease. J Alzheimers Dis 59, 265-275.


[4] Uchiyama K, Muramatsu N, Yano M, Usui T, Miyata H, Sakaguchi S. (2013) Prions disturb post-Golgi trafficking of membrane proteins. Nat Commun 4, 1846.