Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type

doi:10.1016/S0006-8993(99)01220-2

Brain Research

Volume 824, Issue 2, 10 April 1999, Pages 300-303

https://doi.org/10.1016/S0006-8993(99)01220-2 Get rights and content

Abstract

Cyclic AMP (cAMP) is disrupted in the brain in dementia of the Alzheimer type (DAT). We investigated whether the cAMP reduction is accompanied by an alteration in the cAMP response element binding protein (CREB) downstream in DAT and control hippocampi. Immunoreactivity of pCREB was significantly decreased in DAT, while total CREB level was unchanged. These findings indicate that impaired cAMP signaling may contribute to the pathophysiology of the disease.

Section snippets

Acknowledgements

We thank Drs. E. Hashimoto, D. Blum-Degen and K. Double for their helpful suggestions. This study was supported by fellowships from the German Ministry for Research and Technology (to P. Riederer and to M. Rösler), the Scientific Research Fund of the Ministry of Education, Science and Culture of Japan (to H. Ozawa) and the grant on Affective Disorders and Brain Science Research of the Ministry of Health and Welfare of Japan (to H. Ozawa).

References (14)

M. Asanuma et al.
Alterations of cAMP response element-binding activity in the aged rat brain in response to administration of rolipram, a cAMP-specific phosphodiesterase inhibitor
Brain Res. Mol. Brain Res.
(1996)
H. Bito et al.
CREB phosphorylation and dephosphorylation: a Ca²⁺- and stimulus duration-dependent switch for hippocampal gene expression
Cell
(1996)
R. Bourtchuladze et al.
Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein
Cell
(1994)
D.A. Frank et al.
CREB: a mediator of long-term memory from mollusks to mammals
Cell
(1994)
H.S. Phillips et al.
BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease
Neuron
(1991)
A. Schnecko et al.
Adenylyl cyclase activity in Alzheimer's disease brain: stimulatory and inhibitory signal transduction pathways are differently affected
Brain Res.
(1994)
R.F. Cowburn et al.
Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer's disease
J. Neurochem.
(1992)

There are more references available in the full text version of this article.

Cited by (190)

CREB: A multifaceted transcriptional regulator of neural and immune function in CNS tumors
2024, Brain, Behavior, and Immunity
Cancers of the central nervous system (CNS) are unique with respect to their tumor microenvironment. Such a status is due to immune-privilege and the cellular behaviors within a highly networked, neural-rich milieu. During tumor development in the CNS, neural, immune and cancer cells establish complex cell-to-cell communication networks which mimic physiological functions, including paracrine signaling and synapse-like formations. This crosstalk regulates diverse pathological functions contributing to tumor progression. In the CNS, regulation of physiological and pathological functions relies on various cell signaling and transcription programs. At the core of these events lies the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a master transcriptional regulator in the CNS. CREB is a kinase inducible transcription factor which regulates many CNS functions, including neurogenesis, neuronal survival, neuronal activation and long-term memory. Here, we discuss how CREB-regulated mechanisms operating in diverse cell types, which control development and function of the CNS, are co-opted in CNS tumors.
The action of phosphodiesterase-5 inhibitors on β-amyloid pathology and cognition in experimental Alzheimer's disease: A systematic review
2023, Life Sciences
Alzheimer's disease (AD) is the most frequent cause of dementia worldwide. The etiology of AD is partially explained by the deposition of β-amyloid in the brain. Despite extensive research on the pathogenesis of AD, the current treatments are ineffective. Here, we systematically reviewed studies that investigated whether phosphodiesterase 5 inhibitors (PDE5i) are efficient in reducing the β-amyloid load in hippocampi and improving cognitive decline in rodent models with β-amyloid accumulation. We identified ten original studies, which used rodent models with β-amyloid accumulation, were treated with PDE5i, and β-amyloid was measured in the hippocampi. PDE5i was efficient in reducing the β-amyloid levels, except for one study that exclusively used female rodents and the treatment did not affect β-amyloid levels. Interestingly, PDE5i prevented cognitive decline in all studies. This study supports the potential therapeutic use of PDE5i for the reduction of the β-amyloid load in hippocampi and cognitive decline. However, we highlight the importance of conducting additional experimental studies to evaluate the PDE5i-related molecular mechanisms involved in β-amyloid removal in male and female animals.
Potential role of IP3/Ca<sup>2+</sup> signaling and phosphodiesterases: Relevance to neurodegeneration in Alzheimer's disease and possible therapeutic strategies
2022, Biochemical Pharmacology
Despite large investments by industry and governments, no disease-modifying medications for the treatment of patients with Alzheimer's disease (AD) have been found. The failures of various clinical trials indicate the need for a more in-depth understanding of the pathophysiology of AD and for innovative therapeutic strategies for its treatment. Here, we review the rational for targeting IP3 signaling, cytosolic calcium dysregulation, phosphodiesterases (PDEs), and secondary messengers like cGMP and cAMP, as well as their correlations with the pathophysiology of AD. Various drugs targeting these signaling cascades are still in pre-clinical and clinical trials which support the ideas presented in this article. Further, we describe different molecular mechanisms and medications currently being used in various pre-clinical and clinical trials involving IP3/Ca⁺² signaling. We also highlight various isoforms, as well as the functions and pharmacology of the PDEs broadly expressed in different parts of the brain and attempt to unravel the potential benefits of PDE inhibitors for use as novel medications to alleviate the pathogenesis of AD.
Calcineurin in development and disease
2022, Genes and Diseases
Calcineurin (CaN) is a unique calcium (Ca²⁺) and calmodulin (CaM)-dependent serine/threonine phosphatase that becomes activated in the presence of increased intracellular Ca²⁺ level. CaN then functions to dephosphorylate target substrates including various transcription factors, receptors, and channels. Once activated, the CaN signaling pathway participates in the development of multiple organs as well as the onset and progression of various diseases via regulation of different cellular processes. Here, we review current literature regarding the structural and functional properties of CaN, highlighting its crucial role in the development and pathogenesis of immune system disorders, neurodegenerative diseases, kidney disease, cardiomyopathy and cancer.
Nrf2 improves hippocampal synaptic plasticity, learning and memory through the circ-Vps41/miR-26a-5p/CaMKIV regulatory network
2022, Experimental Neurology
Citation Excerpt :
These intracellular events eventually trigger an increase in the cascade of synaptic proteins and promote hippocampal circuits. Furthermore, some studies have suggested that the level of phosphorylated CREB at Ser133 (p-CREB) is significantly decreased in the AD hippocampus (Yamamoto-Sasaki et al., 1999; Liu et al., 2018). Thus, p-CREB and CREB were tested by western blot and IFC after circ-Vps41 was knocked down or overexpressed in HT22 cells.
Antioxidant response transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2/Nfe2l2) is a neuroprotective agent in learning and memory impairment. This study provides a new perspective to explore the regulatory mechanisms of Nrf2. Here, we found that Nrf2 regulated circular RNA circ-Vps41 to increase hippocampal synaptic plasticity; Nrf2 bound the Vps41 promoter to activate transcription of the Vps41 gene and promote expression of circ-Vps41; circ-Vps41 positively correlated with Nrf2, synaptic plasticity, and learning and memory but negatively correlated with reactive oxygen species; and Nrf2 promoted CaMKIV expression by increasing levels of circ-Vps41, which can absorb miR-26a-5p that targets CaMKIV. Our findings revealed a new circRNA-based regulatory network regulated by Nrf2 and provided novel insights into the potential mechanism involved in the improvement of learning and memory impairment.
The detrimental effects of APOE4 on risk for Alzheimer's disease may result from altered dendritic spine density, synaptic proteins, and estrogen receptor alpha
2022, Neurobiology of Aging
Women carriers of APOE4, the greatest genetic risk factor for late-onset Alzheimer's disease (AD), are at highest risk of developing AD, yet factors underlying interactions between APOE4 and sex are not well characterized. Here, we examined how sex and APOE3 or APOE4 genotypes modulate object and spatial memory, dendritic spine density and branching, and protein expression in 6-month-old male and female E3FAD and E4FAD mice (APOE^+/+/5xFAD^+/−). APOE4 negatively impacted object recognition and spatial memory, with male E3FADs exhibiting the best memory across 2 object-based tasks. In both sexes, APOE4 reduced basal dendritic spine density in the medial prefrontal cortex and dorsal hippocampus. APOE4 reduced dorsal hippocampal levels of PDS-95, synaptophysin, and phospho-CREB, yet increased levels of ERα. E4FAD females exhibited strikingly increased GFAP levels, in addition to the lowest levels of PSD-95 and pCREB. Overall, our results suggest that APOE4 negatively impacts object memory, dendritic spine density, and levels of hippocampal synaptic proteins and ERα. However, the general lack of sex differences or sex by genotype interactions suggests that the sex-specific effects of APOE4 on AD risk may be related to factors unexplored in the present study.

View all citing articles on Scopus

View full text

Short communicationImpaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type

Abstract

Section snippets

Acknowledgements

Brain Res. Mol. Brain Res.

Cell

Cell

Cell

Neuron

Brain Res.

Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer's disease

J. Neurochem.

Short communication
Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer type