BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases

Lu, Bai; Nagappan, Guhan; Guan, Xiao-Ming; Nathan, Pradeep J.; Wren, Paul

doi:10.1038/nrn3505

Cited by 595 publications

(449 citation statements)

References 231 publications

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“…The current observation that BDNF Met 66 in preclinical ADAD was associated with increased tau, hippocampal dysfunction and memory impairment is consistent with the role that CNS BDNF plays in synaptic excitation, long-term potentiation and neuronal plasticity (Hariri et al, 2003;Peng et al, 2005;Garzon and Fahnestock, 2007;Forlenza et al, 2010;Fahnestock, 2011;Lee et al, 2012;Lu et al, 2013). Evidence of a mechanistic relationship between BDNF and tau has been shown in cellular studies that demonstrate that BDNF can induce rapid dephosphorylation of tau through TrkB activation (Elliott et al, 2005) and that BDNF loss in Alzheimer's disease is specific to tangle-bearing neurons (Ferrer et al, 1999).…”

Section: Discussionsupporting

confidence: 53%

“…This characteristic pathological process manifests initially as cognitive impairment, which increases progressively so eventually classification of dementia is warranted (Hardy and Higgins, 1992;Ittner and Gö tz, 2011;Spires-Jones and Hyman, 2014). Clinical pathological relationships in Alzheimer's disease are still not understood completely; however, recent in vitro (Hariri et al, 2003;Lee et al, 2012), post-mortem (Peng et al, 2005;Garzon and Fahnestock, 2007;Buchman et al, 2016) and animal (Caccamo et al, 2010;Lee et al, 2012;Rosa and Fahnestock, 2015) studies suggest neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) moderate neuronal and synaptic dysfunction and their behavioural expression in Alzheimer's disease (Fahnestock, 2011;Lu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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) for a scientific commentary on this article. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-b-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-b in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) "4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation noncarriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val 66 homozygotes, 48 Met 66 carriers). Among preclinical mutation carriers, Met 66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val 66 homozygotes. Cortical amyloid-b and cerebrospinal fluid amyloidb 42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val 66 homozygotes and Met 66 carriers. There was an effect of APOE on amyloid-b levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-b on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met 66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-b in autosomal dominant Alzheimer's disease.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Lim

Hassenstab

Cruchaga

et al. 2016

Brain

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“…32 BDNF also has a pivotal role in learning and memory. 33 This highlights the potentially neuroprotective effect of elevated NGF and BDNF signaling seen in HA mice and may partially explain the improved motor and cognitive performance of HA mice and the loss of this effect when PD123319 was administered.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

Umschweif

Shabashov²,

Alexandrovich³

et al. 2014

J Cereb Blood Flow Metab

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Long-term exposure of mice to mild heat (341C±11C) confers neuroprotection against traumatic brain injury (TBI); however, the underling mechanisms are not fully understood. Heat acclimation (HA) increases hypothalamic angiotensin II receptor type 2 (AT 2 ) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brain AT 2 receptor confers protection against several types of brain pathologies, including ischemia, a hallmark of the secondary injury occurring following TBI. As AT 2 activates the same pro-survival pathways involved in HA-mediated neuroprotection (e.g., Akt phosphorylation, hypoxia-inducible factor 1a (HIF-1a), and brain-derived neurotrophic factor (BDNF)), we examined the role of AT 2 in HA-mediated neuroprotection after TBI. Using an AT 2 -specific antagonist PD123319, we found that the improvements in motor and cognitive recovery as well as reduced lesion volume and neurogenesis seen in HA mice were all diminished by AT 2 inhibition, whereas no significant alternations were observed in control mice. We also found that nerve growth factor/tropomyosin-related kinase receptor A (TrkA), BDNF/TrkB, and HIF-1a pathways are upregulated by HA and inhibited on PD123319 administration, suggesting that these pathways play a role in AT 2 signaling in HA mice. In conclusion, AT 2 is involved in HA-mediated neuroprotection, and AT 2 activation may be protective and should be considered a novel drug target in the treatment of TBI patients.

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“…Indeed, genetic and/or pharmacological manipulations of either BDNF or TrkB levels impaired (120)(121)(122)(123)(124)(125) or ameliorated (126)(127)(128)(129)(130) neuronal plasticity and hippocampusdependent memory. BDNF has been implicated in a vast array of neurological disorders, including AD (85,(131)(132)(133)(134)(135)(136). Interestingly, a recent study showed that BDNF delivered after disease onset reversed pathology in an AD model (137).…”

Section: Potential Mediators Of Xbp1 Signaling In Neuronsmentioning

confidence: 99%

“…Given the diversity of extrinsic and intrinsic factors controlling their structure, shape, dynamic, elimination and remodeling, it is not surprising that numerous molecules regulate their complex architecture and function (83,84). There are three main aspects of modulating synapse function: (1) promotion of synaptic transmission by enhancing transmitter release or blocking transmitter degradation and/or reuptake, (2) facilitation of synaptic plasticity by changing neuronal activity, and (3) stimulation of synaptogenesis by promoting the growth of new terminals or strengthening the existing pre-and postsynaptic structures by neurotrophic factors (85). For instance, XBP1 modulates many molecules involved in spine morphogenesis and memory function, including but not limited to Cdk5 (24,86), BDNF (26) and Kalirin-7 (87).…”

Section: Potential Mediators Of Xbp1 Signaling In Neuronsmentioning

confidence: 99%

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

Cissé

Duplan

Checler

2016

Mol Med

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X-box binding protein 1 (XBP1) is a unique basic region leucine zipper transcription factor that was isolated two decades ago in a search for regulators of major histocompatibility complex class II gene expression. XBP1 is a very complex protein that regulates many physiological functions, including the immune system, inflammatory responses and lipid metabolism. Evidence over the past few years suggests that XBP1 also plays an important role in pathological settings, since its activity as a transcription factor has profound effects on the prognosis and progression of diseases such as cancer, neurodegeneration and diabetes. Here we provide an overview of recent advances in our understanding of this multifaceted molecule, particularly in regulating synaptic plasticity and memory function, and the implications in neurodegenerative diseases, with an emphasis on Alzheimer's disease.

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BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases

Cited by 595 publications

References 231 publications

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

BDNFVal66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer’s disease

Neuroprotection after Traumatic Brain Injury in Heat-Acclimated Mice Involves Induced Neurogenesis and Activation of Angiotensin Receptor Type 2 Signaling

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

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