Near infrared light decreases synaptic vulnerability to amyloid beta oligomers

Comerota, Michele M.; Krishnan, Balaji; Taglialatela, Giulio

doi:10.1038/s41598-017-15357-x

Cited by 43 publications

(56 citation statements)

References 55 publications

(62 reference statements)

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“…In addition, this decrease seems to include monomeric tau, which can act as seeds for the formation of oligomeric tau suggesting this decrease in total tau may be beneficial [ 34 ]. Thus, unlike our previous results in which we found that NIR light induces a selective reduction of Aβ oligomers at the synapses in the human amyloid precursor protein (APP) overexpressing mouse model, Tg2576 [ 19 ], the tau reduction in the hippocampus and cortex of NIR light-treated hTau mice that we observed in the present study is not limited to the synaptic region, but rather occurs throughout the brain parenchyma. Nonetheless, this molecular phenomenon of overall reduced tau oligomers translates into a functional benefit as illustrated by the observed memory improvement in the novel object recognition (NOR) test of hTau mice that received the NIR light treatment.…”

Section: Discussioncontrasting

confidence: 99%

“…We found that both total and oligomeric tau was reduced in the synaptic compartment as well as in the total protein extract in 3xTgAD mice, whereas the Aβ was reduced exclusively at the synapses. This is similar to what we observed here in the hTau mice, as well as we previously reported in the Tg2576 mice [ 19 ]. Our results thus suggest that the NIR light-induced mitigation of Aβ and tau pathology is sufficient and equally effective when the two amyloid proteins coexist in a system, supporting NIR light as a promising treatment for AD.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have found a reduction of hyperphosphorylated tau and NFTs in NIR light-treated K369I mice [ 15 ], a model of frontotemporal dementia [ 16 ]. In addition, we and others have previously shown a direct effect of NIR light in reducing pathological Aβ accumulations in transgenic mouse models of APP overexpression and further described increased synaptic resilience to the binding and dysfunctional impact Aβ oligomers in NIR light-treated mice [ 15 , 17 – 19 ]. Despite this suggestive initial evidence, however, the effect of NIR light on levels of total and synaptic tau oligomers as well as synaptic tau oligomer-induced functional changes remains unknown.…”

Section: Introductionmentioning

confidence: 91%

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Near Infrared Light Treatment Reduces Synaptic Levels of Toxic Tau Oligomers in Two Transgenic Mouse Models of Human Tauopathies

et al. 2018

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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.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 91%

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Near Infrared Light Treatment Reduces Synaptic Levels of Toxic Tau Oligomers in Two Transgenic Mouse Models of Human Tauopathies

et al. 2018

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“…To confirm protein changes using immunoblotting, the isolation of synaptosomes was performed using Syn-PER Synaptic Protein Extraction Reagent (ThermoFisher Scientific) as described previously [39], followed by ultracentrifugation to obtain PSD fractions. Similarly to sucrose gradient protocol described above, the hippocampal tissue was homogenized using a Dounce glass homogenizer in Syn-PER Reagent and centrifuged at 1,200× g for 10 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Zolochevska

Bjorklund

Woltjer

et al. 2018

JAD

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Some individuals, here referred to as Non-Demented with Alzheimer’s Neuropathology (NDAN), retain their cognitive function despite the presence of amyloid plaques and tau tangles typical of symptomatic Alzheimer’s disease (AD). In NDAN, unlike AD, toxic amyloid-β oligomers do not localize to the postsynaptic densities (PSDs). Synaptic resistance to amyloid-β in NDAN may thus enable these individuals to remain cognitively intact despite the AD-like pathology. The mechanism(s) responsible for this resistance remains unresolved and understanding such protective biological processes could reveal novel targets for the development of effective treatments for AD. The present study uses a proteomic approach to compare the hippocampal postsynaptic densities of NDAN, AD, and healthy age-matched persons to identify protein signatures characteristic for these groups. Subcellular fractionation followed by 2D gel electrophoresis and mass spectrometry were used to analyze the PSDs. We describe fifteen proteins which comprise the unique proteomic signature of NDAN PSDs, thus setting them apart from control subjects and AD patients.

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“…We assessed the early events of AD-like synapse dysfunction/memory using our well-established biochemical, behavioral, and electrophysiological studies in our laboratory [27]. We observed a marked enhancement in the phosphorylation at threonine 147 of PLD1 in the oAb-incubated slices compared to controls (Fig.…”

Section: Increased Pld1 Expression Observed In Response To Oab Acutementioning

confidence: 96%

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Krishnan

Kayed

Taglialatela

2018

A&D Transl Res & Clin Interv

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IntroductionPhospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies.MethodsSynaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition.ResultsWe observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice.DiscussionUsing human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.

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Near infrared light decreases synaptic vulnerability to amyloid beta oligomers

Cited by 43 publications

References 55 publications

Near Infrared Light Treatment Reduces Synaptic Levels of Toxic Tau Oligomers in Two Transgenic Mouse Models of Human Tauopathies

Near Infrared Light Treatment Reduces Synaptic Levels of Toxic Tau Oligomers in Two Transgenic Mouse Models of Human Tauopathies

Postsynaptic Proteome of Non-Demented Individuals with Alzheimer’s Disease Neuropathology

Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

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