Identifying high efficacy potential targets in Alzheimer’s disease by a mechanistic comparison with prion diseases

Prion diseases and Alzheimer’s disease share many similarities in seeding activity, symptomatic and pathological presentations, and mechanisms of neurodegeneration. Accordingly, it is pertinent to inquire whether Alzheimer’s should be considered; and therefore treated like; a prion disease. This mental framework would likely guide many to target the seeding of Alzheimer’s as a method for altering disease progression. This review cross examines both diseases to dissect the limits to their overlap and understand how these similarities can be exploited for more effective treatment. While conventional wisdom has chosen to focus on the common seeding properties in each disease, this review concludes that targeting seeding in Alzheimer’s disease would not be as effective in treating it; as opposed to targeting seeding in prion diseases. Seeding in prion diseases drives conversion from the antiapoptotic cellular Prion Protein (PrPc) to toxic scrapie Prion Protein (PrPsc). While seeding of amyloid-β in Alzheimer’s does not drive such analogous conversion of benign monomers to a toxic state. The seeding activity of hyperphosphorylated tau (HPT) in Alzheimer’s does. This implies promise for using anti-aggregation therapies effective for PrPsc in taupathies, on HPT in Alzheimer’s. However, given that this event is downstream of amyloid-β seeding and that tau can become toxic through other means, even modulating HPT seeding may not be as effective a therapeutic target in Alzheimer’s, as it may be in prion diseases. The intracellular interactions of amyloid-β and HPT exploit similar pathways in triggering apoptosis as in PrPsc. Thus, therapeutics that target these common pathways would be effective in both diseases. Additionally, while PrPc has been shown to contribute to amyloid-β toxicity, this review suggests that blocking the binding between the two proteins via allosteric or competitive inhibitors, rather than completely eradicating PrPc, would be the most optimal treatment. Such a therapy could also be applied to PrPc/PrPsc binding in prion diseases. Such a change in the thinking framework could significantly increase druggable targets for both prion and Alzheimer’s therapeutics. This could also expand the relevancy of niche fields of study, like mitochondrial dynamics, from application to a singular disease, to multiple diseases.