Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells (original) (raw)
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CREB expression mediates amyloid β-induced basal BDNF downregulation
Neurobiology of Aging, 2015
In Alzheimer's disease, accumulation of amyloid-b (Ab) is associated with loss of brain-derived neurotrophic factor (BDNF), synapses, and memory. Previous work demonstrated that Ab decreases activityinduced BDNF transcription by regulating cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation. However, the specific mechanism by which Ab reduces basal BDNF expression remains unclear. Differentiated, unstimulated human neuroblastoma (SH-SY5Y) cells treated with oligomeric Ab exhibited significantly reduced CREB messenger RNA compared with controls. Phosphorylated and total CREB proteins were decreased in both the cytoplasm and nucleus of Ab-treated cells. However, neither pCREB129 nor pCREB133 levels were altered relative to total CREB levels. The protein kinase A activator forskolin increased pCREB133 levels and prevented Ab-induced basal BDNF loss when administered before Ab but did not rescue BDNF expression when administered later. These data demonstrate a new mechanism for Ab-induced BDNF downregulation: in the absence of cell stimulation, Ab downregulates basal BDNF levels via Ab-induced CREB transcriptional downregulation, not changes in CREB phosphorylation. Thus, Ab reduces basal and activity-induced BDNF expression by different mechanisms.
Oligomers of beta-amyloid peptide inhibit BDNF-induced arc expression in cultured cortical Neurons
Current Alzheimer research, 2007
The progressive memory loss observed in Alzheimer's disease (AD) is accompanied by an increase in the levels of amyloid-peptide (A ) and a block of synaptic plasticity. Both synaptic plasticity and memory require changes in the expression of synaptic proteins such as the activity-regulated cytoskeleton-associated protein, Arc (also termed Arg3.1). Using a model of synaptic plasticity in which BDNF increases Arc expression in cultured cortical neurons, we have found that an oligomeric form of A strongly inhibits the BDNF-induced increase of Arc expression. Given that A oligomers are likely to be involved in the synaptic dysfunction and cognitive impairment observed in amyloid depositing mouse models, we hypothesize that inhibition of Arc induction by BDNF contributes to the synaptic and memory deficits at early stages of AD.
Alzheimer's & Dementia, 2011
Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies investigating the effects of the b-amyloid (Ab) peptide on neurogenesis have been inconclusive, since both neurogenic and neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric Ab 1-40 and Ab 1-42 (nM-mM concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied real time quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric Ab 1-40 increased the number of functional neurons, whereas oligomeric Ab 1-42 suppressed the number of functional neurons. Interestingly, oligomeric Ab exposure did not influence the number of hES cell-derived neurons compared with untreated cells, while in contrast fibrillar Ab 1-40 and Ab 1-42 induced gliogenesis. These findings indicate that Ab 1-42 oligomers may impair the function of stem cellderived neurons. We propose that it may be possible for future AD therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with trophic support and by targeting different aggregation forms of Ab.
PLoS ONE, 2013
Brain-derived neurotrophic factor (BDNF) importantly regulates learning and memory and supports the survival of injured neurons. Reduced BDNF levels have been detected in the brains of Alzheimer's disease (AD) patients but the exact role of BDNF in the pathophysiology of the disorder remains obscure. We have recently shown that reduced signaling of BDNF receptor TrkB aggravates memory impairment in APPswe/PS1dE9 (APdE9) mice, a model of AD. The present study examined the influence of Bdnf gene deficiency (heterozygous knockout) on spatial learning, spontaneous exploratory activity and motor coordination/balance in middle-aged male and female APdE9 mice. We also studied brain BDNF protein levels in APdE9 mice in different ages showing progressive amyloid pathology. Both APdE9 and Bdnf mutations impaired spatial learning in males and showed a similar trend in females. Importantly, the effect was additive, so that double mutant mice performed the worst. However, APdE9 and Bdnf mutations influenced spontaneous locomotion in contrasting ways, such that locomotor hyperactivity observed in APdE9 mice was normalized by Bdnf deficiency. Obesity associated with Bdnf deficiency did not account for the reduced hyperactivity in double mutant mice. Bdnf deficiency did not alter amyloid plaque formation in APdE9 mice. Before plaque formation (3 months), BDNF protein levels where either reduced (female) or unaltered (male) in the APdE9 mouse cortex. Unexpectedly, this was followed by an age-dependent increase in mature BDNF protein. Bdnf mRNA and phospho-TrkB levels remained unaltered in the cortical tissue samples of middle-aged APdE9 mice. Immunohistological studies revealed increased BDNF immunoreactivity around amyloid plaques indicating that the plaques may sequester BDNF protein and prevent it from activating TrkB. If similar BDNF accumulation happens in human AD brains, it would suggest that functional BDNF levels in the AD brains are even lower than reported, which could partially contribute to learning and memory problems of AD patients. Citation: Rantamäki T, Kemppainen S, Autio H, Stavén S, Koivisto H, et al. (2013) The Impact of Bdnf Gene Deficiency to the Memory Impairment and Brain Pathology of APPswe/PS1dE9 Mouse Model of Alzheimer's Disease. PLoS ONE 8(7): e68722.
Advances in Clinical and Experimental Medicine, 2023
Background. The pathophysiology of Alzheimer's disease (AD) is not fully understood and that new biomarkers for the condition should be presented. Objectives. Our study aimed to determine the blood levels of some biochemical molecules and peptide proteins in AD, which is accepted as the most common cause of dementia in the world, and to elucidate the relationship between them. Materials and methods. The study consisted of 2 groups: 40 newly diagnosed AD patients and 40 healthy individuals. Plasma levels between the 2 groups and the correlation between them were statistically analyzed. Results. The median brain-derived neurotrophic factor (BDNF) level in the AD group was found to be higher and statistically significant compared to the control group (p = 0.033). Conclusions. According to our literature review, this is the first article in which these molecules have been studied together in AD patients. In this study, we revealed the importance of these parameters and especially the instrumental role of BDNF in the form and function of the brain in AD patients. Interestingly, in the patient group, all parameters in our study showed a positive and significant positive relationship with one another (p < 0.001).
Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early in the progression of Alzheimer’s disease (AD). Since BDNF plays a critical role in neuronal survival, synaptic plasticity, and memory, BDNF reduction may contribute to synaptic and cellular loss and memory deficits characteristic of AD. In vitro evidence suggests that amyloid- (A) contributes to BDNF downregulation in AD, but the specific A aggregation state responsible for this downregulation in vivo is unknown. In the present study, we examined cortical levels of BDNF mRNA in three different transgenic AD mouse models harboring mutations in APP resulting in A overproduction, and in a genetic mouse model of Down syndrome. Two of the three A transgenic strains (APPNLh and TgCRND8) exhibited significantly decreased cortical BDNF mRNA levels compared with wild-type mice, whereas neither the other strain (APPswe/ PS-1) nor the Down syndrome mouse model (Ts65Dn) was affected. Only APPNLh and TgCRND8 mice expressed high A42/A40 ratios and larger SDS-stable A oligomers (115 kDa). TgCRND8 mice exhibited downregulation of BDNF transcripts III and IV; transcript IV is also downregulated in AD. Furthermore, in all transgenic mouse strains, there was a correlation between levels of large oligomers, A42/A40 , and severity of BDNF decrease. These data show that the amount and species of A vary among transgenic mouse models of AD and are negatively correlated with BDNF levels. These findings also suggest that the effect of A on decreased BDNF expression is specific to the aggregation state of A and is dependent on large oligomers.
Targeting Brain-Derived Neurotrophic Factor (BDNF) - An Important Strategy to Alzheimer's Disease
Journal of Pharmaceutical and Medicinal Research, 2021
Many theories have been proposed to explain why candidate disease-modifying drugs (DMTs) for Alzheimer's disease (AD) failed. Late initiation of treatments during AD development, inappropriate drug dosages, incorrect selection of main therapeutic targets, and primarily inadequate understanding of the complex pathophysiology of AD are the most prominent ones. Reduced expression of Brain Derived Neurotrophic Factor (BDNF) is essential in the pathogenesis of Alzheimer's disease. BDNF plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. It can be a novel target for the treatment of the disease. In Alzheimer's disease, the hippocampus, parietal, entorhinal, and frontal cortex all have the most extreme BDNF deficits. Lower levels of BDNF can be linked to neuronal death, masking any gene-related effects. High BDNF levels have been attributed to a lower risk of dementia and Alzheimer's. Improvements in BDNF levels imparted by exe...
Brain, Behavior, and Immunity, 2013
Dendritic cells (DCs), the main actors of immune responses and inflammation, may play a role in Alzheimer's disease (AD). Recent studies demonstrate that monocyte-derived DCs (MDDCs), generated in vitro in the presence of amyloid b 1-42 peptide (Ab 1-42), show a functional alteration and an increased production of inflammatory molecules. Accordingly, MDDCs from AD patients show a more pronounced proinflammatory profile than DCs obtained from control subjects. In this study, we aimed at further investigating DC role in AD. Thus, we analyzed the in vitro effect of Ab 1-42 treatment on already differentiated DCs from AD patients, as compared to control subjects. We found that Ab 1-42 significantly decreases the expression of brain-derived neurotrophic factor (BDNF) in DCs derived from AD patients but not from control subjects. Thus, possibly due to their Ab-induced reduction of neurotrophic support to neurons, DCs from AD patients might contribute to brain damage by playing a part in Ab-dependent neuronal toxicity.
Neurotrophic factors and Alzheimer's disease: are we focusing on the wrong molecule?
Journal of neural transmission. Supplementum, 2002
Brain derived neurotrophic factor (BDNF) promotes cholinergic neuron function and survival. In Alzheimer's disease, BDNF mRNA and protein are decreased in basal forebrain cholinergic neuron target tissues such as cortex and hippocampus. Using RT-PCR, we demonstrate that BDNF is synthesized in basal forebrain, supplying cholinergic neurons with a local as well as a target-derived source of this factor. BDNF mRNA levels are decreased 50% in nucleus basalis of Alzheimer disease patients compared to controls. Thus, not only do the basal forebrain cholinergic neurons have a reduced supply of target-derived BDNF, but also of local BDNF. We also show by Western blotting that human CNS tissue contains both proBDNF and mature BDNF protein. Moreover, we demonstrate a significant (2.25-fold) deficit in proBDNF protein in Alzheimer's disease parietal cortex compared to controls. Thus, reduced BDNF mRNA and protein levels in Alzheimer's disease suggests that BDNF administration may b...