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Moving Away from the Tau/Amyloid-β Debate: New Perspectives in Alzheimer’s Disease Research


Alessandra Costanza1, Constantin Bouras1, Eniko Kövari1, and 
Panteleimon Giannakopoulos1,2


The two core pathological hallmarks of Alzheimer’s disease (AD) are insoluble amyloid-β (Aβ) deposits, referred to as senile plaques (SPs), and neurofibrillary tangles (NFTs) composed of abnormally phosphorylated tau protein aggregates [1,2]. The mechanisms of SP and NFT formation and their role in the pathophysiology of AD is an area of great controversy. According to the amyloid cascade hypothesis, accumulation of insoluble Aβ in the brain is the primary event driving AD pathogenesis [3]. Traditionally, the increase of soluble Aβ production has been attributed to the well-described alterations in amyloid precursor protein (APP) processing into Aβ peptides (Aβ1–40 and Aβ1–42), influenced by the patterns of proteolytic cleavage by α, β, and γ secretases [4]. The disruption of the imbalance between the total load of Aβ production and clearance is followed by the progressive aggregation of SPs in the extracellular space, which triggers synaptic dysfunction and neuronal cell death. Recent observations focused on Aβ oligomer toxicity postulate that SPs may represent the brain’s effort to control the deleterious effect of soluble Aβ byproducts [5–11]. In spite of several hypotheses suggesting that misfolded Aβ species initiate cellular events that result in later tau aggregation, the pathways linking Aβ and tau remain poorly understood [6,11–17].

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