Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease

Kumar, Kushal; Kumar, Ashwani; Keegan, Richard M.; Deshmukh, Rahul

doi:10.1016/j.biopha.2017.12.053

Cited by 133 publications

(103 citation statements)

References 140 publications

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“…NMDAR and BDNF of hippocampus play a pivotal role of synaptic plasticity in the hippocampus [13]. Rao et al observed that the expression of BDNF in AD brains is decreased and NMDAR-medicated excitotoxicity play a key role in the development of AD [16]. The results of our study showed that in memory-impaired AD-rats induced by AlCl 3 , S. betaceum administration decrease the level of NMDAR significantly with p=0.006 (p<0.05), but did not change the level of BDNF with p=0.280 (p>0.05).…”

Section: Resultsmentioning

confidence: 99%

“…Brain-derived neurotrophic factor (BDNF) is one of the fundamental neurotrophic factor in learning and memory, particularly expressed ubiquitous in the brain and playing a key regulator role of development, cognition and plasticity of the hippocampus [9,[11][12][13][14][15]. BDNF, a synaptic plasticity marker, is important for long-term potentiation (LTP) like mediating the regulation of excitatory synapses during early LTP [13,16]. BDNF is secreted at pre-or postsynaptic areas.…”

Section: Introductionmentioning

confidence: 99%

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Solanum Betaceum Improves Cognitive Function by Decreasing N-Methyl-D-Aspartate on Alzheimer Rats Model

et al. 2019

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Objective: The purpose of this study was to evaluate the effect of Solanum betaceum towards cognitive function, i.e. memory, and the level of N-Methyl-D-Aspartate receptor (NMDAR) and brain derived neurothropic factor (BDNF) as a drug candidate therapy for Alzheimer rats model.Methods: Fifty adult male albino rats were divided into five groups (K0, K1, P1, P2 and P3). Four groups (K1, P1, P2 and P3) of Alzheimer’s disease(AD) rats were induced by aluminum chloride with dose 2 g/L for 21 days period and three groups (P1, P2 and P3) in 22th day administered parallellywith 100 mg/kg b.w/day; 200 mg/kg b.w/day; and 400 mg/kg b.w/day of S. betaceum respectively for14 days. The level of NMDAR and BDNF wasmeasured by enzyme-linked immunosorbent assay methods, whereas memory was measured by the Morris water maze test.Results: S. betaceum administration increased cognitive function significantly (p=0.037) of AD induced-rats by decreasing the time to reach the targetof Morris water maze and maintaining the low levels of NMDAR significantly (p=0.006), but the level of BDNF did not increase significantly (p=0.346).These results indicated that ethanol extracts of S. betaceum could decrease brain NMDAR and increase cognitive function by promote better memoryfunction but did not significant increased the level of BDNF in AD-induced rats.Conclusion: This study revealed that the treatment of AD-induced rats with S. betaceum extracts significantly improve memory function and decreasethe level of NMDAR.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Solanum Betaceum Improves Cognitive Function by Decreasing N-Methyl-D-Aspartate on Alzheimer Rats Model

et al. 2019

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“…Treatment options for Alzheimer's disease are limited, and there are currently only two classes of medications approved by the Food and Drug Administration (FDA): cholinesterase inhibitors (eg, donepezil, rivastigmine, and galantamine) and the N ‐methyl‐d‐aspartate receptor antagonist memantine . At best, these medications have shown modest symptomatic improvements in cognitive functioning, daily functioning, and behavior but do little to slow the cognitive and functional decline . As the number of people with Alzheimer's disease in the United States is expected to increase from about 6 million to approximately 14 million by the year 2050 with costs of care increasing from around $290 billion to $1.1 trillion in that time frame, there has never been a more urgent need for treatment that can slow or reverse the Alzheimer's disease process…”

Section: Decision‐making In Clinical Trials For Alzheimer's Diseasementioning

confidence: 99%

“…15 At best, these medications have shown modest symptomatic improvements in cognitive functioning, daily functioning, and behavior but do little to slow the cognitive and functional decline. 15,17 As the number of people with Alzheimer's disease in the United States is expected to increase from about 6 million to approximately 14 million by the year 2050 with costs of care increasing from around $290 billion to $1.1 trillion in that time frame, there has never been a more urgent need for treatment that can slow or reverse the Alzheimer's disease process. 18 Significant resources and funding are being devoted to clinical research trials to identify better symptomatic treatments and ultimately disease-modifying treatments for Alzheimer's disease.…”

Section: Decision-making In Clinical Trials For Alzheimer's Diseasementioning

confidence: 99%

Informed consent, therapeutic misconception, and clinical trials for Alzheimer's disease

Wilkins

Forester

2020

Int J Geriat Psychiatry

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“…Despite advances in the understanding of the physiopathology of AD [17], there are no efficient therapies to date. Although limitations in culturing brain-derived live neurons might slow AD research, the rapid advances in cellular genetic reprogramming, in particular the induction of somatic cells (e.g., fibroblast) into stem cells (e.g., human induced pluripotent stem cells, hiPSCs), has led to the modeling of FAD PSEN1 mutations in vitro [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

Soto-Mercado

Mendivil-Perez

Vélez-Pardo

et al. 2019

Preprint

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive disturbance as a consequence of the loss of cholinergic neurons in the brain, neuritic plaques and hyperphosphorylation of TAU protein. Although the underlying mechanisms leading to these events are unclear, mutations in presenilin 1 (PSEN1), e.g., E280A (PSEN1 E280A), are causative factors for autosomal dominant early-onset familial AD (FAD). Despite advances in the understanding of the physiopathology of AD, there are no efficient therapies to date. Limitations in culturing brain-derived live neurons might explain the limited effectiveness of AD research. Here, we show that mesenchymal stromal (stem) cells (MSCs) can be used to model FAD, providing novel opportunities to study cellular mechanisms and to establish therapeutic strategies.Indeed, we cultured MSCs with the FAD mutation PSEN1 E280A and wild-type (WT) PSEN1 from umbilical cords and characterized the transdifferentiation of these cells into cholinergic-like neurons (ChLNs). PSEN1 E280A ChLNs but not WT PSEN1 ChLNs exhibited increased intra-and extracellular A42 peptide and TAU phosphorylation (at residues Ser202/Thr205), recapitulating the molecular pathogenesis of FAD caused by mutant PSEN1. Furthermore, PSEN1 E280A ChLNs presented oxidative stress (OS) as evidenced by the oxidation of DJ-1Cys106-SH into DJ-1Cys106-SO3 and the detection of DCF-positive cells and apoptosis markers such as activated pro-apoptosis proteins p53, c-JUN, PUMA and CASPASE-3 and the concomitant loss of the mitochondrial membrane potential and DNA fragmentation. Additionally, mutant ChLNs displayed Ca2+ flux dysregulation and deficient acetylcholinesterase (AChE) activity compared to control ChLNs. Interestingly, the inhibitor JNK SP600125 almost completely blocked TAU phosphorylation. Our findings demonstrate that FAD MSC-derived cholinergic neurons with the PSEN1 E280A mutation are a valid model of AD and provide important clues for the identification of targetable pathological molecules.

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Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease

Cited by 133 publications

References 140 publications

Solanum Betaceum Improves Cognitive Function by Decreasing N-Methyl-D-Aspartate on Alzheimer Rats Model

Solanum Betaceum Improves Cognitive Function by Decreasing N-Methyl-D-Aspartate on Alzheimer Rats Model

Informed consent, therapeutic misconception, and clinical trials for Alzheimer's disease

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

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