F4‐02‐03: Lithium Treatment of Agitation in Alzheimer's Disease (Lit‐ad): Clinical Rationale and Study Design

Devanand, Davangere P.; Strickler, Jesse G.; Crocco, Elizabeth; Forester, Brent P.; Husain, Mustafa M.; Vahia, Ipsit V.; Huey, Edward D.; Pelton, Gregory H.

doi:10.1016/j.jalz.2018.06.2870

Cited by 2 publications

(2 citation statements)

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“…In addition, this hyper-reactivity to the light stimulus was abolished using LiCl treatment. This observation was consistent with data obtained in rodent models and patients [55,56]. Actually, a recent open label clinical trial in Alzheimer's disease patients showed that a low dose of lithium may represent an effective treatment for agitation symptoms.…”

Section: Discussionsupporting

confidence: 91%

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model

Barbereau

Yehya

Silhol

et al. 2020

Pharmacological Research

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Brain-derived neurotrophic factor (BDNF) dysregulations contribute to the neurotoxicity in neurodegenerative pathologies and could be efficiently targeted by therapies. In Alzheimer's disease (AD), although the relationship between BDNF and amyloid load has been extensively studied, how Tau pathology affects BDNF signaling remains unclear. Using the TAU-P301L transgenic zebrafish line, we investigated how early Tau-induced neurotoxicity modifies BDNF signaling. Alterations in BDNF expression levels were observed as early as 48 h post fertilization in TAU-P301L zebrafish embryos while TrkB expression was not modified. Decreasing BDNF expression, using a knockdown strategy in wild-type embryos to mimic Tau-associated decrease, did not modify receptor expression but promoted neurotoxicity as seen by axonal outgrowth shortening and neuronal cell death. Moreover, the TrkB antagonist ANA-12 reduced the length of axonal projections. Rescue experiments with exogenous BDNF partially corrected neuronal alterations in TAU-P301L by counteracting primary axonal growth impairment but without effect on apoptosis. Importantly, the axonal rescue was proved functionally effective in a behavioral test, at a similar level as obtained with the GSK3b inhibitor LiCl, used as positive control. Finally, treatment with a TrkB agonist, 7,8-dihydroxyflavone, gave comparable results and allowed full rescue of locomotor response. We provided here strong evidences that Tau neurotoxicity provoked alterations in BDNF system and that BDNF pathway might represent an efficient therapeutic target.

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Section: Discussionsupporting

confidence: 91%

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model

Barbereau

Yehya

Silhol

et al. 2020

Pharmacological Research

View full text Add to dashboard Cite

show abstract

“…Accordingly, evidence exists that drugs used for psychiatric disorders may provide benefit to AD patients, through the modulation of BDNF levels. To this end, recent evidence has shown that lithium, the drug of choice for bipolar disorder, may be used for agitation in AD [70]. Notably, chronic micro-doses of lithium prevented memory loss and neuro-histopathological changes in a transgenic murine model of AD through BDNF up-regulation, an effect that was associated with a less anxious state [71].…”

Section: Pharmacologic Modulationmentioning

confidence: 99%

Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer’s Disease

2020

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Alzheimer's disease (AD) is a chronic, neurodegenerative and devastating disorder affecting a high percentage of the population over 65 years of age and causing a relevant emotional, social and economic burden. Clinically, it is characterized by a prominent cognitive deficit associated with language and behavioral impairments. The molecular pathogenesis of AD is multifaceted and involves changes in neurotransmitter levels together with alterations of inflammatory, oxidative, hormonal and synaptic pathways, which may represent a druggable target for both prevention and treatment; however, an effective treatment for AD still represents an unmet goal.Since neurotrophic factors participate in the modulation of the above-mentioned pathways, they have been pointed out as critical contributors of AD etiology, whose modulation might be beneficial for AD. We here focused on the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) providing several lines of evidence pointing to BDNF as a plausible endophenotype of cognitive deficit in AD, illustrating some among the most recent possibilities to modulate the expression of this neurotrophin in the brain in an attempt to ameliorate cognition and delay the progression of AD.This review shows that otherwise disparate pharmacologic or non-pharmacologic approaches converge on BDNF providing a means whereby apparently unrelated medical approaches may nevertheless produce similar synaptic and cognitive outcomes in AD pathogenesis through its modulation, suggesting that BDNF-based synaptic repair may represent a modifying strategy to ameliorate cognition in AD. Key points:1) The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) represents a plausible endophenotype of cognitive deficit in Alzheimer's disease (AD) and a mechanistic underpinning to be targeted to offset the cognitive decline of AD.2) Otherwise disparate pharmacologic or non-pharmacologic approaches converge on BDNF, influencing synaptic plasticity and ameliorating the cognitive deficit 3) BDNF-based synaptic repair may represent an interesting modifying strategy to improve cognition in AD patients.

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F4‐02‐03: Lithium Treatment of Agitation in Alzheimer's Disease (Lit‐ad): Clinical Rationale and Study Design

Cited by 2 publications

References 0 publications

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model

Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model

Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer’s Disease

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