Brain-derived neurotrophic factor is reduced in Alzheimer's disease

Connor, Bronwen; Young, Deborah; Qiao, Yan; Faull, Richard L.M.; Synek, Beth J.; Dragunow, Michael

doi:10.1016/s0169-328x(97)00125-3

Cited by 538 publications

(326 citation statements)

References 79 publications

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“…S6). These results are consistent with previous reports of reduced BDNF levels in AD brains and other animal models (27)(28)(29). We next assessed how BDNF protein levels change in response to CBP gene transfer.…”

supporting

confidence: 90%

“…The role of CREB in cognition is well established; it is thought that, once activated, CREB facilitates the transcription of key proteins necessary for activity-dependent plasticity (19). One of these proteins is brain-derived neurotrophic factor (BDNF), which is known to facilitate synaptic plasticity and memory formation (26) and has been proposed to play a role in the pathogenesis of AD, with reduced BDNF levels detected in AD brains (27,28). Thus, we next sought to determine whether the improvement in learning and memory following CBP gene transfer might be linked to an increased BDNF level in the hippocampus.…”

mentioning

confidence: 99%

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P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

Caccamo

Oddo

2013

Alzheimer's & Dementia

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Cognitive dysfunction and memory loss are common features of Alzheimer's disease (AD). Abnormalities in the expression profile of immediate early genes that play a critical role in memory formation, such as the cAMP-response element binding protein (CREB), have been reported in the brains of AD patients. Here we show that amyloid-β (Aβ) accumulation, which plays a primary role in the cognitive deficits of AD, interferes with CREB activity. We further show that restoring CREB function via brain viral delivery of the CREB-binding protein (CBP) improves learning and memory deficits in an animal model of AD. Notably, such improvements occur without changes in Aβ and tau pathology, and instead are linked to an increased level of brain-derived neurotrophic factor. The resulting data suggest that Aβ-induced learning and memory deficits are mediated by alterations in CREB function, based on the finding that restoring CREB activity by directly modulating CBP levels in the brains of adult mice is sufficient to ameliorate learning and memory. Therefore, increasing CBP expression in adult brains may be a valid therapeutic approach not only for AD, but also for various brain disorders characterized by alterations in immediate early genes, further supporting the concept that viral vector delivery may be a viable therapeutic approach in neurodegenerative diseases.tangles | presenilin

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supporting

confidence: 90%

mentioning

confidence: 99%

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

Caccamo

Oddo

2013

Alzheimer's & Dementia

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“…Reduced levels of BDNF are observed in the striatum and the hippocampus in patients suffering from HD and AD, respectively 37,38 . Polymorphisms in the gene encoding BDNF have been positively associated with age of onset of AD in some studies 39,4041 , although this association is controversial [42][43][44] .…”

Section: Increasing Bdnf As a Therapeutic Approachmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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“…This raises the questions of whether levels of the one known positive LTP modulator, BDNF, decline with age, and, in particular, are reduced in middle-aged animals. Although hippocampal BDNF gene expression is consistently found to be decreased in Alzheimer's disease (Phillips et al, 1991;Murray et al, 1994;Connor et al, 1997), reports of age effects on BDNF expression in rodents have been mixed. Hattiangady and colleagues (2005) found hippocampal BDNF immunoreactivity was significantly reduced from young adulthood to middle age (4 versus 12 months) with no further change afterwards in male Fischer 344 rats.…”

Section: Causes Of Age-related Changes In Synaptic Plasticitymentioning

confidence: 99%

Synaptic plasticity in early aging

Lynch

Rex

Gall

2006

Ageing Research Reviews

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Studies of how aging affects brain plasticity have largely focused on old animals. However, deterioration of memory begins well in advance of old age in animals, including humans; the present review is concerned with the possibility that changes in synaptic plasticity, as found in the long-term potentiation (LTP) effect, are responsible for this. Recent results indicate that impairments to LTP are in fact present by early middle age in rats but only in certain dendritic domains. The search for the origins of these early aging effects necessarily involves ongoing analyses of how LTP is induced, expressed, and stabilized. Such work points to the conclusion that cellular mechanisms responsible for LTP are redundant and modulated both positively and negatively by factors released during induction of potentiation. Tests for causes of the localized failure of LTP during early aging suggest that the problem lies in excessive activity of a negative modulator. The view of LTP as having redundant and modulated substrates also suggests a number of approaches for reversing age-related losses. Particular attention will be given to the idea that induction of brain-derived neurotrophic factor, an extremely potent positive modulator, can be used to provide long periods of normal plasticity with very brief pharmacological interventions. The review concludes with a consideration of how the selective, regional deficits in LTP found in early middle age might be related to the global phenomenon of brain aging. #

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Brain-derived neurotrophic factor is reduced in Alzheimer's disease

Cited by 538 publications

References 79 publications

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Synaptic plasticity in early aging

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