Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice

Xie, Youmie; Seawell, Jaimie; Boesch, Emily; Allen, Lauren; Suchy, Ashley; Longo, Frank M.; Meeker, Rick B.

doi:10.1016/j.expneurol.2020.113489

Cited by 15 publications

(12 citation statements)

References 117 publications

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“…Mouse ages were selected from prior work that associates human age with murine development, finding one year of human life equivalent to nine days in the moues during adulthood [ 105 ]. These ages are consistent with prior work comparing young adult and middle-aged mice [ 106 – 108 ].…”

Section: Methodssupporting

confidence: 91%

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

Qraeya

Mahdi

Kaufman

et al. 2022

Aging

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In the U.S. about half of the HIV-infected individuals are aged 50 and older. In men living with HIV, secondary hypogonadism is common and occurs earlier than in seronegative men, and its prevalence increases with age. While the mechanisms(s) are unknown, the HIV-1 trans-activator of transcription (Tat) protein disrupts neuroendocrine function in mice partly by dysregulating mitochondria and neurosteroidogenesis. We hypothesized that conditional Tat expression in middle-aged male transgenic mice [Tat(+)] would promote age-related comorbidities compared to age-matched controls [Tat(−)]. We expected Tat to alter steroid hormone milieu consistent with behavioral deficits. Middle-aged Tat(+) mice had lower circulating testosterone and progesterone than age-matched controls and greater circulating corticosterone and central allopregnanolone than other groups. Young Tat(+) mice had greater circulating progesterone and estradiol-to-testosterone ratios. Older age or Tat exposure increased anxiety-like behavior (open field; elevated plus-maze), increased cognitive errors (radial arm water maze), and reduced grip strength. Young Tat(+), or middle-aged Tat(−), males had higher mechanical nociceptive thresholds than age-matched counterparts. Steroid levels correlated with behaviors. Thus, Tat may contribute to HIV-accelerated aging.

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Section: Methodssupporting

confidence: 91%

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

Qraeya

Mahdi

Kaufman

et al. 2022

Aging

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“…In addition, upregulation of p75 NTR in gp120-treated cells and gp120-tg mice has been shown to cause a synaptic loss in the striatum. Moreover, using small molecules to block proBDNF from binding to p75 NTR has been shown to lower the neurodegeneration events observed in gp120-tg mice ( Xie et al, 2021 ). Interestingly, p75 NTR is shown to induce ICER in cultured hippocampal neurons, and ICER can heterodimerize with CREB and block CREB-induced transcription of several genes, including BDNF ( Thomas et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

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“…It also needs to be ascertained if LM11A-31 is similarly effective in female mice. However, with regard to sex, LM11A-31 is similarly effective at reversing pathology in males and females in a mouse model of AD (Simmons et al, 2014), protects against neurodegeneration in both male and female HIV gp120 transgenic mice (Xie et al, 2021), and also protects against cisplatin induced peripheral neuropathy in both male and female mice (Friesland et al, 2014). Therefore, a sex difference is not expected.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, LM11A-31 has shown therapeutic effects in multiple animal models of neurological diseases, including post-traumatic brain injury (Shi et al, 2013), human immunodeficiency virus (HIV) related dementia (Meeker et al, 2016;Fogle et al, 2021;Xie et al, 2021), contusion spinal cord injury (Tep et al, 2013), Huntington's disease (Simmons et al, 2016;Simmons et al, 2021), and AD (Knowles et al, 2013;Nguyen et al, 2014;Simmons et al, 2014;Yang et al, 2020a). In AD, LM11A-31 has been shown to be efficacious in male and female mice and in two different mouse models of AD (Simmons et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery

Nguyen

Crumpacker

Calderon

et al. 2021

J Pharmacol Exp Ther

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The aim of this study was to test whether post-stroke oral administration of a small molecule p75 neurotrophin receptor (p75 NTR ) modulator (LM11A-31) can augment neuronal survival and improve recovery in a mouse model of stroke. Mice were administered LM11A-31 for up to 12 weeks, beginning 1 week after stroke. Metabolomic analysis revealed that after 2 weeks of daily treatment, mice that received LM11A-31 were distinct from vehicle treated mice by principal component analysis and had higher levels of serotonin, acetylcholine, and dopamine in their ipsilateral hemisphere. LM11A-31 treatment also improved redox homeostasis by restoring reduced glutathione. It also offset a stroke induced reduction in glycolysis by increasing acetyl-CoA. There was no effect on cytokine levels in the infarct. At 13 weeks following stroke, adaptive immune cell infiltration in the infarct was unchanged in LM11A-31 treated mice, indicating that LM11A-31 does not alter the chronic inflammatory response to stroke at the site of the infarct. However, LM11A-31 treated mice had less brain atrophy, neurodegeneration, tau pathology, and microglial activation in other regions of the ipsilateral hemisphere. These findings correlated with improved recovery of motor function on a ladder test, improved sensorimotor and cognitive abilities on a nest construction test, and less impulsivity in an open field test. These data support small molecule modulation of the p75 neurotrophin receptor for preserving neuronal health and function during stroke recovery. SIGNIFICANCE STATEMENTThe findings from this study introduce the p75 neurotrophin receptor as a novel small molecule target for promotion of stroke recovery. Given that LM11A-31 is in clinical trials as a potential therapy for Alzheimer's disease, it could be considered as a candidate for assessment in stroke or vascular dementia studies.

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Small molecule modulation of the p75 neurotrophin receptor suppresses age- and genotype-associated neurodegeneration in HIV gp120 transgenic mice

Cited by 15 publications

References 117 publications

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Post-Stroke Administration of the p75 Neurotrophin Receptor Modulator, LM11A-31, Attenuates Chronic Changes in Brain Metabolism, Increases Neurotransmitter Levels, and Improves Recovery

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