Abstract
The concurrent application of subtoxic doses of soluble oligomeric forms of human amyloid-beta (oAβ) and Tau (oTau) proteins impairs memory and its electrophysiological surrogate long-term potentiation (LTP), effects that may be mediated by intra-neuronal oligomers uptake. Intrigued by these findings, we investigated whether oAβ and oTau share a common mechanism when they impair memory and LTP in mice. We found that as already shown for oAβ, also oTau can bind to amyloid precursor protein (APP). Moreover, efficient intra-neuronal uptake of oAβ and oTau requires expression of APP. Finally, the toxic effect of both extracellular oAβ and oTau on memory and LTP is dependent upon APP since APP-KO mice were resistant to oAβ- and oTau-induced defects in spatial/associative memory and LTP. Thus, APP might serve as a common therapeutic target against Alzheimer's Disease (AD) and a host of other neurodegenerative diseases characterized by abnormal levels of Aβ and/or Tau.
Highlights
Protein aggregation and deposition have been considered key pathogenetic processes in several neurodegenerative disorders, including Alzheimer’s Disease (AD), tauopathies, Parkinson’s Disease, Huntington disease and many others (Shelkovnikova et al, 2012; Takalo et al, 2013)
We utilized membrane fractions from HEK293 cells stably transfected with human amyloid precursor protein (APP) with the Swedish mutation (APPSw) and incubated with/out oTau derived from recombinant 4R/2N Tau protein
When the same treatment was applied to APP knock-out (APP-KO) cultures we found that 73 ± 5% of total cells internalized Ab (n = 112; t test: t(98) = 2.734; p=0.007 comparing APP-KO vs. wild type (WT) cells) and a markedly lower mean number of fluorescent spots (2.9 ± 0.2; t(191) = 4.508; p
Summary
Protein aggregation and deposition have been considered key pathogenetic processes in several neurodegenerative disorders, including Alzheimer’s Disease (AD), tauopathies, Parkinson’s Disease, Huntington disease and many others (Shelkovnikova et al, 2012; Takalo et al, 2013). Soluble small aggregates of these proteins have gained a lot of attention in studies aimed at understanding the etiopathogenesis of these diseases. This is evident in AD, in which the abnormal increases of the levels of amyloid-beta (Ab) and Tau proteins and their aggregation are crucial steps in the chain of events leading to dementia (Irvine et al, 2008; Kopeikina et al, 2012). The importance of soluble oligomeric forms of Ab (oAb) and Tau (oTau) has been corroborated by numerous evidences demonstrating their presence in human cerebrospinal fluid in healthy
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