Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide

Chohan, Muhammad Omar; Li, Bin; Blanchard, Julie; Tung, Yunn Chyn; Heaney, Agnes T.; Rabe, Ausma; Iqbal, Khalid; Grundke‐Iqbal, Inge

doi:10.1016/j.neurobiolaging.2009.08.008

Cited by 68 publications

(65 citation statements)

References 59 publications

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“…The DG sub-region maintains glutamate levels in tauopathy mice. Future studies should consider using GluCEST imaging to monitor the health of the DG as a potential region for neurogenic therapy (30). …”

Section: Discussionmentioning

confidence: 99%

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

et al. 2014

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Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer’s disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is using proton magnetic resonance spectroscopy (1H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional 1H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy were carried out on tau transgenic mice with the P301S mutation (PS19, n=9) and their wild-type littermates (WT, n=8), followed by immunohistochemistry of their brain tissue. GluCEST imaging resolution allowed for sub-hippocampal analysis of glutamate. Glutamate was significantly decreased by 29% in the CA sub-region of the PS19 hippocampus, and by 15% in the thalamus, where synapse loss was also measured. Glutamate levels and synapse density remained high in the dentate gyrus sub-region of the hippocampus, where neurogenesis is known to occur. The further development of GluCEST imaging for preclinical applications will be valuable, as therapies are being tested in mouse models of tauopathy.

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Section: Discussionmentioning

confidence: 99%

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

et al. 2014

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“…We previously showed that increase in FGF2 levels inhibits neuronal lineage determination and maturation during neurogenesis, and it can be counteracted by both CNTF and P6 [23]. Our previous studies also showed that LIF, a cytokine, which maintains totipotency of neural stem cells and inhibits neuronal lineage while favoring glial lineage formation [95–99] can be inhibited with P6 [31]. Our data suggest that the levels of various neurotrophic factors are altered in sera from children with autism and this imbalance along with the increased oxidative stress could be among the primary factors responsible for the altered development and neurodegeneration observed in both in vivo and in vitro models.…”

Section: Discussionmentioning

confidence: 99%

“…P6 which corresponds to amino acid residues 146–156 of human CNTF was identified as an active region of this neurotrophic factor by epitope mapping of neutralizing antibodies to CNTF, as described before [31–33]. The peptide was synthesized using solid phase peptide synthesis (SPSS) methods, purified by reverse phase HPLC to >96% purity, lyophilized, and characterized via HPLC, NMR, and ESI-MS [31–33].…”

Section: Methodsmentioning

confidence: 99%

“…The peptide was synthesized using solid phase peptide synthesis (SPSS) methods, purified by reverse phase HPLC to >96% purity, lyophilized, and characterized via HPLC, NMR, and ESI-MS [31–33]. …”

Section: Methodsmentioning

confidence: 99%

“…Besides, recombinant CNTF was shown to cause anorexia, skeletal muscle loss, hyperalgesia, severe cramps, and muscle pain in human clinical trials [30]. Previously, by mapping the biologically active region of human CNTF, we generated an 11-mer peptide, Peptide 6 (P6), which is blood-brain barrier (BBB) permeable, has a plasma half-life of over 6 hr, and does not cause adverse effects associated with the full-length protein in mice or rats [31–35]. This CNTF derived small peptide mimetic is shown to exert beneficial effect on neurogenesis, neuronal and synaptic plasticity, and cognition via inhibition of LIF signaling pathway and elevation of BDNF level by increasing its transcription [31,35].…”

Section: Introductionmentioning

confidence: 99%

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Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

et al. 2015

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Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

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Tau and Alzheimer's disease: Past, present and future

Iqbal

2023

Cytoskeleton

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My journey with tau started when in 1974 for the first time I isolated neurofibrillary tangles of paired helical filaments (PHFs) from autopsied Alzheimer's disease (AD) brains and discovered that they were made up of a ~50–70 KDa protein on SDS‐polyacrylamide gels. Subsequently my team discovered that this PHF protein and the microtubule‐associated factor called tau were one and the same protein. However, we found that tau in neurofibrillary tangles/PHFs in AD brain was abnormally hyperphosphorylated, and unlike normal tau, which promoted the assembly of tubulin into microtubules, the AD‐hyperphosphorylated tau inhibited microtubule assembly. These discoveries of tau pathology in AD opened a new and a major area of research on tau and on the molecular pathology of this major cause of dementia in middle‐ and old‐age individuals. Tau pathology, which without fail is made up of the aggregated hyperphosphorylated state of the protein, is also the hallmark lesion of a family of around 20 related neurodegenerative diseases, called tauopathies. Currently, tau pathology is a major drug target for the treatment of AD and related tauopathies. Both active and passive tau immunization human clinical trials at various stages are underway. Initial results range from negative to partially promising. Future studies will reveal whether tau therapy alone or in combination with drugs targeting Aβ and/or neurodegeneration will be required to achieve the most effective treatment for AD and related disorders.

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Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide

Cited by 68 publications

References 59 publications

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy

Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

Tau and Alzheimer's disease: Past, present and future

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