Abstract
Tau oligomers are emerging as a key contributor to the synaptic dysfunction that drives cognitive decline associated with the clinical manifestation and progression of Alzheimer’s disease (AD). Accordingly, there is ample consensus that interventions that target tau oligomers may slow or halt the progression of AD. With this ultimate goal in mind, in the present study, we investigated tau oligomer accumulation and its synaptic and behavioral consequences after an in vivo treatment with near infrared (NIR) light (600–1000 nm) in two transgenic mouse models, overexpressing human tau either alone (hTau mice) or in combination with amyloid beta (3xTgAD mice). We found that a 4-week exposure to NIR light (90 s/day/5 days a week) significantly reduced levels of endogenous total and oligomeric tau in both synaptosomes and total protein extracts from the hippocampus and cortex of hTau mice and improved deteriorating memory function. Similar results were observed in the 3xTgAD mice, which further displayed reduced synaptic Aβ after NIR light treatment. On the other hand, ex vivo binding of tau oligomers in isolated synaptosomes as well as tau oligomer-induced depression of long-term potentiation (LTP) in hippocampal slices from NIR light-treated wt mice were unaffected. Finally, levels of proteins critically involved in two mechanisms associated with clearance of misfolded tau, inducible HSP70 and autophagy, were upregulated in NIR light treated mice. Collectively, these results show that NIR light decreases levels of endogenous toxic tau oligomers and alleviate associated memory deficits, thus furthering the development of NIR light as a possible therapeutic for AD.
Highlights
Alzheimer’s disease (AD) is the most frequent age-related dementia, for which there is currently no resolving cure
In the cortical and hippocampal total protein extracts, we found a decrease in tau oligomers in near infrared (NIR) light-treated hTau mice compared to sham-treated control mice
Tau oligomer levels were reduced in synaptosomal fractions of both cortex and hippocampus of NIR light-treated hTau mice compared to the sham-treated mice (Fig. 2c)
Summary
Alzheimer’s disease (AD) is the most frequent age-related dementia, for which there is currently no resolving cure. The accumulation of plaques and neurofibrillary tangles (NFTs) consisting of amyloid beta (Aβ) and hyperphosphorylated tau protein, respectively, are two quintessential hallmarks of AD. Many factors such as mitochondrial dysfunction, neuroinflammation, impaired clearance of dysfunctional proteins, and synaptic retraction contribute to the disease progression [1,2,3,4]. Tau oligomers act in a prion-like manner, seeding the misfolding and aggregation of cellular monomeric tau and resulting in the spreading of the disease from cell to cell [14] Together, this evidence suggests that the targeting of tau oligomer accumulations, at the synapses, will mitigate the synaptic dysfunction and the progression of clinical manifestation of AD
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