Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
This transgenic mouse overexpresses human APP carrying the Swedish mutation. The mouse develops age-related amyloid pathology and cognitive deficits. It does not develop tangle pathology or appreciable neuronal loss (Richardson et al., 2003).
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.
Synaptic Loss
TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.
Neuronal Loss
Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.
Gliosis
Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.
Changes in LTP/LTD
At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).
Cognitive Impairment
Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy
Strain Name: N/A
Summary
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Tangles
Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.
Synaptic Loss
Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).
Neuronal Loss
Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.
Gliosis
At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.
Changes in LTP/LTD
Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.
Cognitive Impairment
Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Summary
Tau264 transgenic mice express low levels of wild-type human tau. This model does not develop neuropathology or behavioral deficits, but can be used to study the interaction of human tau with other proteins, such as Aβ and α-synuclein, by crossbreeding with other mouse models.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
This transgenic mouse expresses human APP with the E693Δ mutation, a deletion mutation associated with early onset Alzheimer’s disease in several Japanese individuals. This mutation, also called the Osaka mutation, involves the in-frame deletion of a codon in exon 17, resulting in a missing glutamate at position 693 in APP, and at position 22 in resulting Aβ peptides.
Phenotype Characterization
When visualized, these models will distributed over a 18 month
timeline
demarcated at the following intervals: 1mo, 3mo, 6mo,
9mo, 12mo, 15mo, 18mo+.
Plaques
Extracelluar amyloid plaques are not observed out to 24 months; however, Aβ accumulates within neurons of the hippocampus and cerebral cortex starting around eight months of age.
Tangles
Overt tangle pathology is not observed out to 24 months of age, but abnormal tau phosphorylation is observed starting around eight months of age.
Synaptic Loss
Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.
Neuronal Loss
Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.
Gliosis
At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.
Changes in LTP/LTD
By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.
Cognitive Impairment
By 8 months of age, transgenic mice exhibit memory impairment in the Morris water maze compared to mice expressing equivalent levels of wild-type human APP.
Last Updated: 28 Sep 2020
Further Reading
No Available Further Reading
Overview
Name: Nimodipine
Synonyms: Nimotop
Chemical Name: 3-(2-methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
Therapy Type: Small Molecule (timeline)
Target Type: Metals
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Discontinued)
Company: Bayer
Approved for: Subarachnoid hemorrhage
Background
Nimodipine is a calcium channel blocker. It is prescribed to prevent vasospasm and possible subsequent stroke in people who have suffered a hemorrhage in the subarachnoid space, the compartment surrounding the brain.
The rationale in evaluating nimodipine capsules in frontotemporal dementia is that it is believed to increase levels of progranulin (see 2012 New York Times story). Plasma and CSF concentrations of this protein are reduced in carriers of pathogenic progranulin mutations, which generally cause progranulin haploinsufficiency and constitute a major genetic cause of FTD (Finch et al., 2009).
Findings
In 2013 and 2014, a pilot trial at the University of California, San Francisco, evaluated nimodipine in eight symptomatic and asymptomatic carriers of loss-of-function mutations in the gene for progranulin. Participants first took escalating doses of nimodipine for a period of four weeks, then the maximum tolerated dose for another four weeks, and then underwent one week of tapering off. This open-label trial aimed primarily to determine the maximum tolerated dose of nimodipine in this patient population as preparation for further efficacy trials. Secondary outcome measures of the trial included plasma progranulin levels measured throughout the trial, CSF progranulin levels measured twice, plasma and CSF cytokine levels, and MRI scan.
The trial was completed in May 2016. As presented at the International Conference on Frontotemporal Dementias, nimodipine was well-tolerated, but did not change progranulin concentrations or alter any of the secondary outcomes (Sep 2016 conference news). Results were subsequently published in a peer-reviewed journal (Sha et al., 2017).
For details, see clinical trials.gov.
Last Updated: 11 Sep 2020
Further Reading
No Available Further Reading
Overview
Name: BI 1181181
Synonyms: VTP 37948, BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Boehringer Ingelheim, Vitae Pharmaceuticals
Background
This compound is an inhibitor targeted to the catalytic site of the enzymes BACE1 and BACE2. It was discovered by the biotechnology company Vitae Pharmaceuticals using Contour®, its structure-based drug design platform, and is being clinically developed with the pharmaceutical firm Boehringer Ingelheim. As with other β-secretase inhibitors, the rationale is to reduce generation of the Aβ peptide and in this way test the amyloid hypothesis of Alzheimer's disease in the clinic. According to the companies, the compound lowers brain Aβ levels in animal models and can be given by mouth; however, no preclinical studies of BI 1181181 have been published in the peer-reviewed literature.
Findings
In 2014, this compound was studied in Phase 1. A first trial evaluated CSF Aβ reduction, as well as safety and pharmacology parameters, of a single tablet in 36 healthy young men in Belgium. A second trial assessed similar parameters of single but rising oral doses in 65 healthy men in Germany. This second study also measured bioavailability of a tablet and powder formulation and the effect of food on the pharmacokinetics of BI 1181181. In October 2014, Vitae Pharmaceuticals declared both trials a success (Oct 2014 news). At AAIC 2015, Boehringer scientists reported the data, showing that BI 1181181 in Phase 1 had dose-dependently reduced plasma and CSF Aβ40 and Aβ42, and had a sufficiently long half-life to support once-daily dosing (see AAIC posters on BI website).
A third Phase 1 study started in November 2014 to study the safety, pharmacokinetics, and pharmacodynamics of a 10-day course of multiple ascending doses in 48 healthy young and old men and women in Germany. In February 2015, Boehringer placed BI 1181181 on hold while investigating skin reactions in some study participants (see Feb 2015 news). A fourth Phase 1 trial was withdrawn before it began enrolling. BI 1181181 was discontinued in favor of a second-generation compound (personal communication, AAIC 2015).
For all clinical trials of this compound, see clinicaltrials.gov.
Last Updated: 09 Oct 2015
Further Reading
No Available Further Reading
Overview
Name: Celecoxib
Synonyms: Celebrex
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pfizer
Approved for: Pain, Arthritis
Background
The NSAID celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, whose anti-inflammatory and analgesic effects partly result from the inhibition of prostaglandin synthesis.
In Alzheimer's research, interest in NSAIDs arose when epidemiological studies started reporting lower rates of Alzheimer's disease, or protection of cognition, among people who had been taking these drugs over long periods of time for the chronic treatment of inflammatory conditions (e.g., Mar 1997 news story; in't Veld et al., 1998; Nov 2001 news story; Vlad et al., 2008; Obermann et al., 2013). Experimental studies supported the argument that inflammation plays a role in Alzheimer's pathogenesis, promptim a wave of clinical trials of various NSAIDs, such as ibuprofen, naproxen, rofecoxib, and R-flurbiprofen. In subsequent years, studies reported Aβ-lowering effects of certain NSAIDS in cell-based and animal models of Alzheimer's disease (e.g., Aug 2000 news story; Sep 2004 news story); celecoxib is not among those.
In May 2014, the FDA approved generic versions of celecoxib (see FDA release). Side effects of this drug are primarily gastrointestinal. All NSAIDs come with a boxed warning to alert health care providers and patients to an increased risk for heart attack and stroke, especially with chronic administration and in patients with pre-existing cardiovascular risk factors.
Findings
Two clinical studies of celecoxib in Alzheimer's disease have been conducted with information available in the public domain.
The first was the Alzheimer's Disease Anti-Inflammatory Prevention Trial, aka ADAPT. Funded by the NIA, in 2001 this primary prevention study started to enroll 2,625 people 70 or older who had a parent or sibling with Alzheimer's or another dementing illness of aging. Conducted at six U.S. sites, this study aimed to determine whether celecoxib or naproxen can delay the onset of AD or age-related cognitive decline. ADAPT was to conduct annual cognitive assessments for five to seven years; however, the trial soon became embroiled in a public controversy (see Sep 2002 news story). In September 2004, Merck withdrew the related NSAID celebrex (Vioxx). In December 2004, the NIA halted dosing in ADAPT over safety concerns, citing an increase in cardiovascular side effects in its naproxen arm (Sep 2004 news story; Dec 2004 news story). A separate report raising concerns about a slightly elevated risk of heart attack with long-term use of certain NSAIDs soon followed, although that report placed the risk with naproxen and rofecoxib higher than with celebrex (Graham et al., 2005). ADAPT safety data were subsequently published but failed to end ongoing controversy over the decision to halt the trial (Nov 2006 news story).
Efficacy data from ADAPT showed that neither celecoxib nor naproxen delayed incident dementia or cognitive decline. Naproxen but not celecoxib was reported to have hastened cognitive decline slightly (ADAPT Research Group, 2007; ADAPT Research Group 2008). ADAPT came to exemplify conflicting findings between observational epidemiology, which continued to report protective effects of NSAIDs on cognition, and RTCs, which were negative (May 2008 news story).
Analysis of ADAPT data continued for some years. A follow-up evaluation of some 1,500 participants in 2010 and 2011 reported that one to three years of preventive treatment with celebrex in people with a family history of AD conferred no protection against cognitive decline (ADAPT Research Group 2013; ADAPT-FS Research Group, 2014 ). Additional analyses attempted to distinguish between slow and fast decliners and to identify a time window during the prodromal phase of AD in which celecoxib might be beneficial. A possible benefit of celecoxib in fast decliners, but not slow decliners, initially did not hold up as a consistent result, and ADAPT overall generated no evidence supporting use of celecoxib for the prevention or treatment of Alzheimer's disease (e.g., Leoutsakos et al., 2011).
Between 2000 and 2005, a study at the University of Los California, Los Angeles, recruited 88 people with mild self-reported memory complaints but normal memory performance scores into a study administering 200 mg or 400 mg of celecoxib daily for 18 months. Forty completed this course of medication. This small study did report group differences in some cognitive parameters and brain imaging favoring the treatment group (Small et al., 2008).
Last Updated: 03 Nov 2014
Further Reading
No Available Further Reading
Overview
Name: AVP-923
Synonyms: Nuedexta, Zenvia
Chemical Name: dextromethorphan hydrobromide/quinidine sulfate
Therapy Type: Combination, Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4), Amyotrophic Lateral Sclerosis (Phase 3), Parkinson's Disease (Phase 3)
Status in Select Countries: Approved in the United States and European Union for treatment of pseudobulbar affect.
Company: Avanir Pharmaceuticals, Otsuka Pharmaceutical Co., Ltd.
Background
AVP-923 is a fixed-dose combination of two approved drugs. One is dextromethorphan, the active ingredient in several brands of cough syrup. Dextromethorphan is a weak antagonist of NMDA receptors, and an agonist of sigma 1 receptors, molecular chaperones located in membranes of the endoplasmic reticulum. The other is quinidine, a drug prescribed to treat irregular heartbeat. Quinidine increases the bioavailability of dextromethorphan by slowing its oxidative metabolism by the liver enzyme cytochrome P450-2D6 and by inhibiting the blood-brain-barrier protein pump P-glycoprotein. Avanir Pharmaceuticals is developing this combination under the name Nuedexta for the treatment of pseudobulbar affect. PBA accompanies primary neurological conditions, such as stroke, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and, less commonly, Alzheimer’s disease. The mechanism of action of AVP-923 on PBA is thought to involve reduction of glutamate excitotoxicity. Nuedexta capsules contain either 20 mg or 30 mg of dextromethorphan hydrobromide with 10 mg of quinidine sulfate.
AVP-923’s safety profile is not benign. It is contraindicated for people with heart problems such as prolonged QT interval, atrioventricular block, and people with a history of thrombocytopenia, hepatitis, bone-marrow depression, or lupus-like syndrome. People who are overly sensitive to dextromethorphan-containing common cough medicines should not take AVP-923. Drug interactions with other CNS drugs, such as monoamine oxidase inhibitors (MAOs) and selective serotonin reuptake inhibitors (SSRIs), are known (Cruz, 2013; Schoedel et al., 2014). Quinidine's effect on P450-2D6 can also affect the pharmacokinetics of some concomitant medications; however, both dextromethorphan and quinidine are used at lower doses in this combination than when prescribed separately for cough or arrhythmia.
Findings
In October 2014, Avanir presented data from a multicenter Phase 2 study at the American Neurological Association annual meeting in Baltimore. Two hundred and twenty people with probable Alzheimer's and clinical agitation were enrolled into a sequential, parallel comparison trial design developed for indications that are prone to placebo effects. In these two-stage trials, a first randomization to drug or placebo is followed by analysis of the placebo group for responders and non-responders, and a subsequent re-randomization of both responders and non-responders to drug or placebo. This minimizes placebo effects during the trial (Ivanova et al., 2011). Two five-week treatment stages exposed 152 participants to 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate, titrated up to 30 and 10 mg, respectively. On the primary outcome, the agitation/aggression domain of the neuropsychiatric inventory (NPI), the AVP-923 group improved 3.3 points compared with 1.7 points for placebo. Secondary outcomes also indicated a drug benefit. Clinicians and caregivers considered the benefit meaningful, according to the presentation. Side effects were in keeping with the combination's known safety profile. Adverse events were more frequent in the treatment group, and most were mild to moderate; serious adverse events were twice as frequent in drug versus placebo group. No deaths occurred in this trial (Sep 2015 news).
At the same conference, results were reported from the dementia cohort of a 750-person, open-label observation study of AVP-923 for the treatment of PBA accompanying dementia, stroke, or traumatic brain injury. This study used no placebo controls but gathered safety, tolerability, and efficacy data on indications poorly represented in the original New Drug Application for AVP-923. It reported a treatment benefit, with side effects within AVP-923's known safety profile (Oct 2014 conference news). A separate open-label safety study giving AVP-923 for a year reported that the combination was generally well-tolerated in a range of neurologic conditions, with serious adverse events consistent with the primary neurological conditions (Pattee et al., 2014).
In 2010, based on positive Phase 3 results, Nuedexta was approved by the U.S. FDA to improve pseudobulbar affect in people with ALS and multiple sclerosis (MS) (Pioro et al., 2010). After ALS patients in that study reported improved speech and swallowing, a subsequent trial confirmed gains in self-reported speech, swallowing, and salivation with drug treatment (Smith et al., 2017).
After its approval, Avanir aggressively promoted Nuedexta to treat disruptive behavior in nursing home residents, although it had not been tested in elderly people. Between 2010 and 2018, the drug was prescribed five times more often to people with PD and/or dementia than to people with ALS or MS (Fralick et al., 2019). Following an investigation by the U.S. Department of Justice, in 2019 Avanir paid $116 million in civil and criminal penalties to settle fraud charges related to illegal marketing of Nuedexta (CNN report).
Avanir is currently developing AVP-786, a second-generation version of Nuedexta, for agitation associated with Alzheimer’s disease.
Nuedexta is also being clinically evaluated for treatment of Huntington's disease. For all trials of AVP-923, see clinicaltrials.gov.
Last Updated: 25 Feb 2020
Further Reading
No Available Further Reading
Cynthia Lemere 
Hiroshi Mori 
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