Intraperitoneal Administration of a Novel TAT-BDNF Peptide Ameliorates Cognitive Impairments via Modulating Multiple Pathways in Two Alzheimer’s Rodent Models

Wu, Yuanyuan; Luo, Xiaobin; Liu, Xinhua; Liu, Deyi; Wang, Xiong; Guo, Ziyuan; Zhu, Ling‐Qiang; Tian, Qing; Yang, Xifei; Wang, Jian‐Zhi

doi:10.1038/srep15032

Cited by 49 publications

(37 citation statements)

References 52 publications

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“…In this study, we found that PGS32 up-regulated the phosphorylation of TrkB. It was reported that compared with the vehicle control rats, p-TrkB was significantly decreased in the scopolamine-infused rats [35] . Galantamine, a cholinergic stimulator used as a positive control, was shown to restore p-TrkB levels and improved cognitive functioning in AD-like rodent models in another study, which is inconsistent with our results.…”

Section: Discussionsupporting

confidence: 48%

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice

et al. 2016

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Aim: Recent studies show that the extract of a Chinese herb Polygalae Radix exerts cognition-enhancing actions in rats and humans. The aim of this study was to characterize the pharmacological profiles of active compounds extracted from Polygalae Radix. Methods: Two fractions P3 and P6 and two compounds PTM-15 and polygalasaponin XXXII (PGS32) were prepared. Neuroprotective effects were evaluated in primary cortical neurons exposed to high concentration glutamate, serum deficiency or H 2 O 2 . Anti-dementia actions were assessed in scopolamine-induced amnesia in mice using step-through avoidance tests and channel water maze tests. After conducting the channel water maze tests, TrkB phosphorylation in mouse hippocampus was detected using Western blotting. Long-term potentiation (LTP) was induced in the dentate gyrus in adult rats; PGS32 (5 μL 400 μmol/L) was injected into the lateral cerebral ventricle 20 min after high frequency stimulation (HFS). Results: Compared to the fraction P6, the fraction P3 showed more prominent neuroprotective effects in vitro and cognitionenhancing effects in scopolamine-induced amnesia in mice. One active compound PGS32 in the fraction P3 exerted potent cognitionenhancing action: oral administration of PGS32 (0.125 mg· kg -1 ·d -1 ) for 19 days abolished scopolamine-induced memory impairment in mice. Furthermore, PGS32 (0.5 and 2 mg· kg -1 ·d -1 ) significantly stimulated the phosphorylation of TrkB in the hippocampus. Intracerebroventricular injection of PGS32 significantly enhanced HFS-induced LTP in the dentate gyrus of rats. Conclusion: PGS32 attenuates scopolamine-induced cognitive impairments in mice, suggesting that it has a potential for the treatment of cognitive dysfunction and dementia.

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Section: Discussionsupporting

confidence: 48%

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice

et al. 2016

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“…The use of TAT as a carrier for brain delivery of drugs has been employed in several experimental approaches for the treatment of AD-like pathology in mouse models 12 13 . Recently, intraperitoneal administration of a TAT-BDNF peptide complex for 1 month was shown to improve the cognitive functions in AD rodent models 23 .…”

Section: Discussionmentioning

confidence: 99%

Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid-β

Fede

Catania

Maderna

et al. 2016

Sci Rep

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We developed a novel therapeutic strategy for Alzheimer’s disease (AD) exploiting the properties of a natural variant of Amyloid-β (Aβ) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aβ, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aβ1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aβ1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aβ toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aβ1-6A2VTAT(D) inhibits Aβ aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AβA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aβ1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aβ production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.

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“…18 Other pathways activated include the mutagen activated protein kinase (Ras-MAPK) signaling which promotes neuronal differentiation, the P13 kinase-AK+ signaling which promotes survival and growth of neurons 19 and the TrKB/ ERK1/2/Ak+ pathway which significantly improves spatial memory. 20 BDNF has also been shown to activate NFkβ which enhances both dendritic spine and excitatory synapse density. 18 Impairment in spatial learning have been seen in mice lacking in NF-kβ subunit.…”

Section: Duration Of Infection 115mentioning

confidence: 99%

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

Michael

Mpofana

Ramlall

et al. 2020

NDT

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Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remains prevalent in the anti-retroviral (ART) era. While there is a complex interplay of many factors in the neuropathogenesis of HAND, decreased neurotrophic synthesis has been shown to contribute to synaptic degeneration which is a hallmark of HAND neuropathology. Brain derived neurotrophic factor (BDNF) is the most abundant and synaptic-promoting neurotrophic factor in the brain and plays a critical role in both learning and memory. Reduced BDNF levels can worsen neurocognitive impairment in HIV-positive individuals across several domains. In this paper, we review the evidence from pre-clinical and clinical studies showing the neuroprotective roles of BDNF against viral proteins, effect on co-morbid mental health disorders, altered human microbiome and ART in HAND management. Potential applications of BDNF modulation in pharmacotherapeutic, cognitive and behavioral interventions in HAND are also discussed. Finally, research gaps and future research direction are identified with the aim of helping researchers to direct efforts to make these BDNF driven interventions improve the quality of life of patients living with HAND.

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Intraperitoneal Administration of a Novel TAT-BDNF Peptide Ameliorates Cognitive Impairments via Modulating Multiple Pathways in Two Alzheimer’s Rodent Models

Cited by 49 publications

References 52 publications

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice

Tackling amyloidogenesis in Alzheimer’s disease with A2V variants of Amyloid-β

<p>The Role of Brain Derived Neurotrophic Factor in HIV-Associated Neurocognitive Disorder: From the Bench-Top to the Bedside</p>

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