Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease

In the paper

“This application scheme resulted in the daily uptake of 14 mg/kg body weight (low dose) and 26 mg/kg body weight during the last phase of the treatment (Figure 4B).”

In the paper

“A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior.”

In the paper

“gliosis being always positively correlated to plaque load.”

In the paper

“Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age.”

• Also stated in: § Quantitative Analysis of Plaque Deposition in 5XFAD Mice · plain

  “Maximal density was not reached even at 14 months of age in females, whereas in males no increase in plaque density was observed after 10 months of age.”

• Also stated in: § Quantitative Analysis of Plaque Deposition in 5XFAD Mice · plain

  “In males, plaque density increased in both brain areas and reached saturation at 10 months of age. In female mice, plaque accumulation was faster, reached higher levels, and continued to increase after 14 months of age.”

In the paper

“Furthermore, β amyloid deposits are usually associated with reactive astrocytes identified by immunohistochemical staining for GFAP (Figure 1G) and microglia identified by isolectin GSA staining (Figure 1H).”

In the paper

“the body weight of transgenic mice was approximately 10% less than that of their control littermates, both, before and after the behavioral tests (Figure 3A)”

In the paper

“As expected, the maximum and average grip strength were significantly higher for males compared to females (F(1,28) = 32.038, p<0.0001; F(1,28) = 25.969, p<0.0001, respectively)”

In the paper

“mock-treated transgenic mice showed less transitions”

In the paper

“treatment with galantamine elevated the preference for the corners to normal levels in a dose dependent manner (Figure 5A)”

In the paper

“treatment with galantamine resulted in increased freezing irrespective of the genotype”

• Also stated in: § Galantamine Treatment Affects Behavior and Plaque Deposition · plain

  “the treatment increased the overall freezing behavior in the fear conditioning paradigm irrespective of the genotype”

In the paper

“reduced avoidance of the center by transgenic mice”

In the paper

“and partially in the light-dark avoidance paradigm”

• Also stated in: § Galantamine Treatment Affects Behavior and Plaque Deposition · plain

  “the abnormal light-dark avoidance behavior of 5XFAD mice was partially normalized.”

In the paper

“The latency at the second encounter with the test box was reduced irrespective of genotype or treatment”

In the paper

“GFAP-positive reactive astrocytes are usually found in association with Aβ plaques (Figure 1).”

In the paper

“and longer presence in the illuminated compartment”

In the paper

“During hippocampus dependent contextual fear conditioning we observed significantly more freezing of 5XFAD mice in the context but also in the neutral surrounding.”

In the paper

“Furthermore, galantamine exerts in cell systems neuroprotective effects by anti-apoptotic action [13], by modulating amyloid precursor processing [14], and by inhibiting β-amyloid aggregation and cytotoxicity [15].”

What the sources say

• Not checked yetcites [13] M Villarroya, 2007, An update on the pharmacology of galantamine, Expert Opin Investig Drugs source
• Not checked yetcites [14] SC Lenzken, 2007, Nicotinic component of galantamine in the regulation of amyloid precursor protein processing, Chem Biol Interact source
• Not checked yetcites [15] B Matharu, 2009, Galantamine inhibits beta-amyloid aggregation and cytotoxicity, J Neurol Sci source

In the paper

“This model recapitulates a variety of AD features, including working memory impairment, reduced anxiety, extensive extracellular plaque formation beginning at 2 months of age, and selective neuron loss, making it a suitable research model for early-onset AD [20]–[24].”

What the sources say

• Not checked yetcites [20]–[24]

In the paper

“by an experimenter not aware of the genotype.”

In the paper

“For the behavioral analysis, sex- and age-matched littermate wild-type mice were used as controls.”

In the paper

“These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.”

• Also stated in: § Introduction · plain

  “Our data show that galantamine slows down plaque deposition and improves behavioral performance.”

In the paper

“In order to normalize regional bias in plaque load, 12 sections 200 µm apart from each other were selected from all animals in every experiment.”

In the paper

“Long-term galantamine treatment of AD patients slows down cognitive and global decline [17] and reduces behavioral symptoms, most strongly in patients with moderate or advanced forms of the disease [18].”

What the sources say

• Not checked yetcites [17] ÅK Wallin, 2011, Galantamine treatment in Alzheimer’s disease: response and long-term outcome in a routine clinical setting, Neuropsychiatr Dis Treat source
• Not checked yetcites [18] S Kavanagh, 2011, Galantamine and behavior in Alzheimer disease: analysis of four trials, Acta Neurol Scand source

In the paper

“Similar long-term positive effects are also reflected in PET measurements [19].”

What the sources say

• Not checked yetcites [19] C Keller, 2011, Long-term effects of galantamine treatment on brain functional activities as measured by PET in Alzheimer’s disease patients, J Alz Dis source

In the paper

“The acetylcholinesterase inhibitors donepezil, galantamine, and rivastigmine serve as first-line symptomatic drug treatment in mild to moderate Alzheimer’s dementia [8].”

What the sources say

• Not checked yetcites [8] L Patel, 2011, Combination therapy for Alzheimer’s disease, Drugs Aging source

In the paper

“Chronic low-level stimulation of nicotinic receptors might up-regulate their expression [10], slow down neurodegeneration [11], and confer protection against β-amyloid toxicity [12].”

What the sources say

• Not checked yetcites [10] X Peng, 1997, Chronic nicotine treatment up-regulates alpha3 and alpha7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y, Mol Pharmacol source
• Not checked yetcites [11] JA Court, 1994, CNS nicotine receptors. Possible therapeutic targets in neurodegenerative disorders, CNS Drugs
• Not checked yetcites [12] T Kihara, 1998, Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity, Brain Res source

In the paper

“Increased production of certain Aβ species, their aggregation, and deposition as insoluble plaques is regarded as an early and key pathology in the development of AD [2].”

What the sources say

• Not checked yetcites [2] M Citron, 2004, Strategies for disease modification in Alzheimer’s disease, Nat Rev Neurosci source

In the paper

“At a systemic level, therapeutic strategies to reverse or prevent Aβ deposits could lead to partial functional restoration of neural circuits [5].”

What the sources say

• Not checked yetcites [5] RB Knowles, 1999, Plaque-induced neurite abnormalities: Implications for disruption of neural networks in Alzheimer’s disease, Proc Natl Acad Sci USA source

In the paper

“Therefore, most AD treatment approaches aim at prevention or reversal of Aβ plaque deposition [6], [7].”

What the sources say

• Not checked yetcites [6] S Schilling, 2008, Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology in vivo, Nat Med source
• Not checked yetcites [7] M Citron, 2010, Alzheimer’s disease: strategies for disease modification, Nat Rev Drug Discov source

In the paper

“However, Aβ deposits are easily identified by immunohistochemistry (Figure 1D) or by thioflavin-S staining (Figure 1F).”

In the paper

“Aβ plaques may serve as reservoirs of soluble Aβ oligomers injuring surrounding neurites and synapses [3], [4].”

What the sources say

• Not checked yetcites [3] RM Koffie, 2009, Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques, Proc Natl Acad Sci USA source
• Not checked yetcites [4] TL Spires, 2005, Dendritic spine abnormalities in APP transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy, J Neurosci source

In the paper

“The amyloid cascade theory provides a rationale for many features of the disease including the pathological markers, the phenotypes caused by autosomal dominant disease genes, and the risk conferred by the APOE gene status [1].”

What the sources say

• Not checked yetcites [1] E Karran, 2011, The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics, Nat Rev Drug Discov source

In the paper

“An improved thioflavin-S staining protocol [32] was used to ensure reduced photobleaching and tissue damage.”

What the sources say

• Not checked yetcites [32] A Sun, 2002, Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections, J Histochem Cytochem source

In the paper

“a number of current strategies e.g. glutaminyl cyclase inhibition and immunotherapy, involved in the treatment and/or prevention of AD progression are indeed directed against the deposition of plaques [6], [57].”

What the sources say

• Not checked yetcites [6] S Schilling, 2008, Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology in vivo, Nat Med source
• Not checked yetcites [57] RB Demattos, 2012, A plaque-specific antibody clears existing β-amyloid plaques in Alzheimer’s disease mice, Neuron source

In the paper

“the positive effect of galantamine in restoring certain normal behavioral traits could result from its acetylcholinesterase inhibitor activity.”

What the sources say

• Not checked yetcites [54] M Singh, 2013, Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection, Eur J Med Chem source

In the paper

“A higher plaque density in female transgenic mice has also been noted in other AD mouse models [33]–[35]”

What the sources say

• Not checked yetcites [33]–[35]

In the paper

“The chronic treatment with galantamine had positive effects on certain behavioral tasks but could not rescue all the abnormalities.”

In the paper

“A previous study by Unger et al. [56] reported that galantamine at a concentration of 2mg/kg injected subcutaneously for 10 days had no effect on the levels of soluble or insoluble forms of Aβ in 10 months old Tg2576 mice.”

What the sources say

• Not checked yetcites [56] C Unger, 2006, Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice, J Pharmacol Exp Ther source

In the paper

“reduced plaque formation could have a role in preventing further cortical atrophy in AD brain, as plaque deposition in multiple studies has been correlated with accelerated cortical atrophy [58], [59].”

What the sources say

• Not checked yetcites [58] JA Becker, 2011, Amyloid-β associated cortical thinning in clinically normal elderly, Ann Neurol source
• Not checked yetcites [59] G Chételat, 2012, Accelerated cortical atrophy in cognitively normal elderly with high β-amyloid deposition, Neurol source

In the paper

“5XFAD mice show at the age of seven months several behavioral deficits, a phenotype with mild cognitive impairment, and progressive amyloid plaque deposition”

In the paper

“we report a significantly delayed progression of amyloid plaque deposition and improvement of certain behavioral symptoms associated with AD in the 5XFAD Alzheimer’s disease model after chronic treatment with galantamine.”

In the paper

“galantamine binds to amyloid oligomers leading to a significant conformational change at the turn region (Asp23-Gly29) disrupting interactions between individual β strands and promoting a nontoxic conformation of Aβ (1–40) to prevent the formation of neurotoxic oligomers [55].”

What the sources say

• Not checked yetcites [55] PPN Rao, 2013, Investigating the binding interactions of galantamine with b-amyloid peptide, Bioorg Med Chem Lett source

In the paper

“in AD loss of pyramidal cells in lamina 2 of the entorhinal cortex and in the CA1 region of the hippocampus was described [39]”

What the sources say

• Not checked yetcites [39] T Gomez-Isla, 1996, Profound Loss of Layer II Entorhinal Cortex Neurons Occurs in Very Mild Alzheimer’s Disease, J Neurosci source

In the paper

“In a similar APP/PS1 transgenic mouse model, sensorimotor gating deficits were reported for aged mice using prepulse inhibition of the acoustic startle response [51].”

What the sources say

• Not checked yetcites [51] H Wang, 2012, Sensorimotor gating and memory deficits in an APP/PS1 double transgenic mouse model of Alzheimer’s disease, Beh Brain Res source

In the paper

“It has also been shown previously, that contextual fear conditioning after 1 footshock is normal in 5XFAD mice younger than 4 months, but impaired in the 6 month old animals, which could be overcome using 3–5 footshocks [48].”

What the sources say

• Not checked yetcites [48] R Kimura, 2009, Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model, Neurobiol Dis source

In the paper

“Likewise, several other AD mouse models display normal motor coordination and grip strength [44].”

What the sources say

• Not checked yetcites [44] SJ Webster, 2013, Comprehensive behavioral characterization of an APP/PS-1 double knock-in mouse model of Alzheimer’s disease, Alzheimers Res Ther source

In the paper

“To mimic the treatment regimen in humans, where the dosage is increased with time to minimize negative side effects [53]”

What the sources say

• Not checked yetcites [53] B Seltzer, 2010, Galantamine-ER for the treatment of mild-to-moderate Alzheimer’s disease, Clin Interv Aging

In the paper

“similar to the tendency to spend longer times in the center of the open field or the open arms of the elevated plus maze reported previously for 5XFAD [22], [23] and several other AD mouse models [45], [46].”

What the sources say

• Not checked yetcites [22] V Shukla, 2013, A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice, FASEB J source
• Not checked yetcites [23] O Wirths, 2010, Identification of low molecular weight pyroglutamate Aβ oligomers in Alzheimer’s disease: a novel tool for therapy and diagnosis, J Biol Chem source
• Not checked yetcites [45] Y Tong, 2010, COL25A1 triggers and promotes Alzheimer’s disease-like pathology in vivo, Neurogenet source

In the paper

“confirming previous studies reporting that 5XFAD mice do not exhibit sensory-motoric impairments in string hanging and beam walking before 9 months [24] or abnormal rota-rod coordination before 12 months [22] of age.”

What the sources say

• Not checked yetcites [24] S Jawhar, 2012, Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer’s disease, Neurobiol Aging 33
• Not checked yetcites [22] V Shukla, 2013, A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer’s disease phenotypes in model mice, FASEB J source

In the paper

“Galantamine is known to have side effects with respect to cholinergically mediated gastrointestinal symptoms like other cholinesterase inhibitors [52].”

What the sources say

• Not checked yetcites [52] D Prvulovic, 2010, Galantamine for Alzheimer’s disease. Expert Opin, Drug Metab Toxicol source

In the paper

“Reduced hippocampus dependent trace fear conditioning, but normal hippocampus independent delay fear conditioning, which is comparable to the tone memory assayed here, has been reported for 5XFAD mice [47].”

What the sources say

• Not checked yetcites [47] M Ohno, 2006, Temporal memory deficits in Alzheimer’s mouse models: rescue by genetic deletion of BACE1, Eur Jour Neurosci source

In the paper

“According to the cholinergic hypothesis, a decreased production of acetylcholine or an amplified acetylcholinesterase activity results in impairment of the cholinergic transmission, in turn leading to the loss of intellectual abilities [54].”

What the sources say

• Not checked yetcites [54] M Singh, 2013, Acetylcholinesterase inhibitors as Alzheimer therapy: From nerve toxins to neuroprotection, Eur J Med Chem source

In the paper

“Suppression of sensorimotor gating has been repeatedly reported in AD patients [49], [50].”

What the sources say

• Not checked yetcites [49] F Jessen, 2001, Sensory Gating Deficit Expressed by a Disturbed Suppression of the P50 Event-Related Potential in Patients With Alzheimer’s Disease, Am J Psychiatry source
• Not checked yetcites [50] I Cancelli, 2006, Sensory gating deficit assessed by P50/Pb middle latency event related potential in Alzheimer’s disease, J Clin Neurophys source

In the paper

“Our paradigm used 2 footshocks, which may have been sufficient to overcome a slight deficit.”