One of the big questions in Alzheimer's research is the degree to which the pathology of dementia results from aggregates of amyloid-β or the neurofibrillary tangles composed of altered forms of tau protein. That question will probably be best and finally answered via the development of therapies that can effectively remove one or the other, but here researchers offer an interesting study carried out in human tissue samples and mice to suggest that the influence of tau is significant:
Amyloid-β (Aβ) was the focus of most of the studies on Alzheimer's disease (AD) in the last 20 years. However, Aβ is not the only pathological agent involved in AD. Microtubule Associated Protein Tau (MAPT) is also likely to play a major role in the disease. While Aβ species derive from APP processing, six tau isoforms are derived from alternative splicing of the MAPT gene transcript in the adult brain. Aβ forms extracellular amyloid plaques, whereas tau forms intracellular insoluble filaments and neurofibrillary tangles (NFTs). In addition, both Aβ and tau form intracellular and extracellular oligomeric species that are soluble pre-fibrillar aggregates, suggesting that the two proteins might share common mechanisms in AD etiopathogenesis.
The prevailing hypothesis in the AD field is that deleterious effects on synaptic function underlying memory loss caused by tau are initiated by Aβ. As AD progresses, tau pathology spreads from the entorhinal cortex in a contiguous, highly selective and highly reproducible fashion, suggesting that extracellular soluble forms of tau transmit pathology from neuron to neighboring neuron. Moreover, once Aβ triggers tau pathology, the disease would progress independent of Aβ. Therefore, therapies targeting Aβ may not be effective once tau pathology is triggered. Nevertheless, tau toxicity does not involve Aβ pathology in tauopathies, suggesting that Aβ is not necessary for tau pathology to occur, and pointing at the need to better clarify the relationship between tau and Aβ.
Here, we investigated whether and how extracellular oligomeric forms of tau (oTau) affect memory and its cellular correlate, long-term potentiation (LTP), either by themselves or in combination with Aβ. We show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment.