Alzheimer's disease (AD) is the most prevalent form of dementia with large impact on population over the age of 65 years . 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 . 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 . 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  and PrPC influence on Aβ and 3PO-tau processing . Although AβOs may lead to memory failure through multiple mechanisms , their interactions with PrPC have been shown to mediate aberrant signaling pathways, synapse loss, and cognitive decline in AD models . 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 . 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 . 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 . 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 , 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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