Species: Mouse
Genes: PSEN1
Modification: PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Amyloid pathology is absent in these mice, but they have impaired neurogenesis. Specifically, the survival of BrdU-labeled neural progenitor cells was impaired leading to fewer newborn neurons. This effect was specific to expression of the mutant PSEN1 in that the survival and differentiation of progenitors in mice overexpressing wild-type human PSEN1 were similar to nontransgenic mice (Wen et al., 2002).
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Overview
Name: Liraglutide
Synonyms: Victoza™, Saxenda™
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Phase 2)
Company: Novo Nordisk A/S
Approved for: Diabetes, weight loss
Background
Liraglutide is an analog of glucagon-like peptide 1. GLP-1 is a hormone that is produced in the gut and activates receptors in the gut, liver, and pancreas to control blood-sugar levels and reduce insulin resistance. Liraglutide and related GLP-1 mimetics cause body weight loss and reduce the risk of cardiovascular events, stroke, and dementia in people with diabetes.
GLP-1 crosses the blood-brain barrier and may improve insulin signaling in the brain (Hölscher, 2018). GLP‐1 was also reported to promote hippocampal synaptic plasticity, cognition, and cell survival (During et al., 2003).
Diabetes, high blood sugar, and insulin resistance are all associated with dementia. In Alzheimer’s disease, there is evidence for insulin resistance in the brain. Thus, there has been much interest in testing liraglutide and other GLP-1 analogs, such as exendin-4, semaglutide, and lixisenatide, as potential therapeutics for AD.
Liraglutide has been tested in preclinical AD models. In the APP/PS1 transgenic mouse, liraglutide reduced amyloid deposition, glial activation, and synapse loss, increased neurogenesis, and improved memory (McClean et al., 2011). Memory reportedly improved regardless of whether liraglutide was given before or after amyloid plaques were established (McClean and Hölscher, 2013; McClean et al., 2015). The same group reported improvements in cerebral blood vessel structure in liraglutide-treated AD mice, resulting in fewer microaneurysms, and less vascular leakage (Kelly et al., 2015). A different group found no effect of liraglutide on amyloid load in the same APP/PS1 model, and one other transgenic model (Hansen et al., 2016). In a mixed model of AD and Type 2 diabetes, liraglutide improved insulin levels, and reduced brain atrophy, amyloid plaque, Aβ aggregates, and tau phosphorylation, while improving cognition (Carranza-Naval et al., 2021).
Liraglutide reduced tau pathology and cognitive impairment in two different models, APP/PS1/Tau triple transgenic mice and mice with Aβ oligomers infused into the brain (Chen et al., 2017; Qi et al., 2016). In mice expressing mutated human tau, the drug reduced phosphorylation of tau and improved a motor phenotype (Hansen et al., 2016). It lessened tau hyperphosphorylation and Aβ overproduction, and normalized insulin signaling in rats with high blood homocysteine, a risk factor for AD (Zhang et al., 2019).
In nonhuman primates, liraglutide partially restored a loss of insulin receptors and synapses caused by Aβ oligomer infusion into the brain (Batista et al., 2018).
Liraglutide also shows activity in mouse models of Parkinson's disease (Liu et al., 2015; Hansen et al., 2016; Badawi et al., 2017), stroke (He et al., 2020), spinal cord injury (Zhang et al., 2020), and traumatic brain injury (Bader et al., 2019).
Among GLP-1 mimetics, liraglutide appears to enter the brain poorly (Salameh et al., 2020).
A peptide drug, liraglutide is injected once a day using a prefilled disposable pen. Gastrointestinal side effects are common, including nausea, diarrhea, vomiting, decreased appetite, indigestion, and constipation. Liraglutide can cause hypoglycemia and dizziness. In mice and rats, liraglutide caused thyroid tumors, and it should not be taken by people at risk for thyroid cancer.
Findings
A study of liraglutide in 34 people with clinically diagnosed AD began in January 2012 at Aarhus University, Denmark. The primary outcome was change in cerebral amyloid deposition, measured by PiB-PET at baseline and after six months of 1.8 mg liraglutide or placebo per day. Secondary outcomes were the Wechsler Memory Scale-IV for cognition and FDG-PET to measure cerebral glucose metabolism (Egefjord et al., 2012). In the study, amyloid load increased and cognition remained unchanged in both liraglutide and placebo groups. FDG-PET declined in the placebo but not in the liraglutide group (May 2016 news on Gejl et al., 2016). Liraglutide boosted FDG-PET in the AD patients by increasing glucose transfer across the blood-brain barrier, restoring it to the level of healthy controls (Gejl et al., 2017).
In August 2013, a trial at Stanford University examined whether liraglutide affected memory in prediabetes. It enrolled 41 people between 50 and 70 who had elevated blood glucose or impaired glucose tolerance. All were cognitively normal, but expressed subjective memory complaints. Half had a family history of dementia. After 12 weeks of 1.8 mg liraglutide daily or placebo, the investigators detected no change in cognition. They did report an improvement in functional MRI measures of brain connectivity in the default mode network, a system affected in AD (Watson et al., 2019).
Another study of similar size, conducted in Italy, compared memory test scores in people with obesity and pre- or early diabetes who lost weight and improved their metabolic profile while taking liraglutide to test scores of people who achieved equivalent weight loss and metabolic changes with diet and lifestyle changes only. The liraglutide group significantly improved on a test of short-term memory and a memory composite, compared to the lifestyle-change-only group (Vadini et al., 2020).
In January 2014, a larger trial in AD started up at Imperial College London. The ELAD study enrolled 204 participants with mild AD dementia but without diabetes for a 12-month course of 1.8 mg liraglutide or placebo per day. The primary outcome was change in FDG-PET. Secondary outcomes included standard clinical and cognitive measures (ADAS-Cog, executive domain scores of the Neuropsychological Test Battery, CDR-SB, and ADCS-ADL), volumetric MRI, as well as changes in PET measures of microglial activation, tau, amyloid, and safety. The protocol is published (Femminella et al., 2019). The trial ended in December 2019. As presented at the 2020 CTAD conference, liraglutide failed on the primary outcome, as no difference in glucose uptake was registered between treatment and placebo groups. Three of five secondary outcomes were improved: The treatment group lost less temporal lobe volume and total brain gray matter volume, and performed better on the ADAS-Exec score, a cognitive outcome that combined the ADAS-Cog and executive domain portions of the NTSB. The CDR-SB and ADCS-ADL were unchanged. The treatment was safe, with fewer serious adverse events in drug versus placebo, and no deaths. Notwithstanding claims of statistical significance on some secondary outcomes, differences between treated and placebo groups were not apparent from data shown at the 2024 AAIC (August 2024 conference news).
In April 2017, a trial at Cedar-Sinai Medical Center, Los Angeles, began recruiting 63 people with Parkinson’s disease to compare a one-year course of up to 1.8 mg liraglutide daily to placebo. The study measured motor, non-motor, and cognitive function. It finished in August 2022. Results posted on clinicaltrials.gov indicate no difference in the primary outcome of the Unified Parkinson’s Disease Rating Scale Part III motor examination between drug and placebo groups. Results are published in preprint form, and claim significant improvements in non-motor symptoms and other secondary outcomes (Hogg et al., 2022).
In May 2019, a trial at Nanjing University Hospital began comparing liraglutide to the antidiabetic medications dapaglifozin and to acarbose, for their effects on cognitive and olfactory function in 36 overweight people whose Type 2 diabetes is poorly controlled with metformin alone. Outcome measures of this 16-week trial included fMRI of odor-induced brain activation, change on the MoCA cognition screen, and an odor detection test. According to published results, liraglutide significantly enhanced odor-induced left hippocampal activation, and improved cognitive subdomains of delayed memory, attention, and executive function. Dapagliflozin and acarbose had no effect (Cheng et al., 2022).
In October 2022, the same group in China began a larger trial, enrolling 324 patients for an eighteen-month treatment with liraglutide, empagliflozin, or the dipeptidyl peptidase-4 inhibitor linagliptin. The latter acts to increase levels of GLP-1. The primary outcome is change in MoCA scores. Secondary outcomes include RBANS, change in olfactory brain activation on MRI, olfactory function, and levels of glycosylated hemoglobin. This trial is slated to finish in December 2026.
Liraglutide is also being evaluated in minor stroke/transient ischemic attack in people with Type 2 diabetes.
For details on liraglutide trials in neurologic indications, see clinicaltrials.gov
Last Updated: 23 Sep 2024
Further Reading
No Available Further Reading
Overview
Name: Epothilone D
Synonyms: BMS-241027
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Bristol-Myers Squibb
Background
BMS-241027 is a small-molecule microtubule stabilizer for the treatment of Alzheimer's disease. One of tau's physiological cellular functions is to bind and stabilize microtubules. This function is lost in tauopathies as hyperphosphorylated and otherwise aberrant tau dissociates from microtubules, leading to neurodegeneration and subsequent cognitive decline. The rationale of BMS-241027 is that stabilizing microtubules may be beneficial in Alzheimer's and other tauopathies.
Unlike other Epothilone D compounds that have been studied in oncology, BMS-241027 is comparably safe and crosses the blood-brain barrier. Epothilone D was shown to be effective at low concentrations (see Brunden et al., 2010).
In rTg4510 mice expressing mutant human tau, BMS-241027 restored a spatial memory deficit. It also reduced hippocampal neuronal loss and various types of histological neuropathology (see Aug 2008 news story). ). In both young and old animals of the (P301S)PS19 tauopathy model, in which tau pathology is developing or well established, respectively, BMS-241027 reversed behavioral and cognitive deficits, cleared tau pathology, and curbed neuron loss (see Hurtado et al., 2010; Mar 2012 news story; Zhang et al., 2012). Dosing young versus old mice serves to model preventive and intervention treatment, respectively.
Findings
In February 2012, Bristol-Myers Squibb started a Phase 1 trial to evaluate the tolerability and pharmacology of BMS-241027 in 40 patients with mild Alzheimer's disease whose MMSE at screening was between 20 and 26. The trial compares 0.003, 0.01, and 0.03 mg/kg infused once a week for nine weeks to placebo. It monitors adverse effects and measures whether the drug changes cerebrospinal fluid (CSF) concentrations of the N-terminal fragment of tau. Secondary endpoints include CSF concentration of the mid-domain tau fragment, cognitive performance on computerized cognitive tests, connectivity MRI, and various pharmacodynamic measures of the drug in plasma. The study ended in October 2013, and evaluation of epothilone D for Alzheimer's disease was subsequently discontinued.
Last Updated: 05 Aug 2014
Further Reading
No Available Further Reading
Overview
Name: AZD3480
Synonyms: ispronicline, TC-1734
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive)
Company: AstraZeneca, Targacept
Last Updated: 17 Oct 2013
Further Reading
No Available Further Reading
Overview
Name: Davunetide
Synonyms: NAP, AL-108
Chemical Name: NAPVSIPQ
Therapy Type: Other
Target Type: Tau (timeline)
Condition(s): Mild Cognitive Impairment, Progressive Supranuclear Palsy, Schizophrenia, Frontotemporal Dementia
U.S. FDA Status: Mild Cognitive Impairment (Discontinued), Progressive Supranuclear Palsy (Discontinued), Schizophrenia (Discontinued), Frontotemporal Dementia (Inactive)
Company: Allon Therapeutics Inc., Paladin Labs Inc.
Background
Davunetide is an intranasal neuropeptide therapy derived from a growth factor called activity-dependent neurotrophic protein (ANAP). Released by glial cells, ANAP contains within it a peptide of the eight amino acids Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln. This peptide has highly potent neuroprotective activity. Published data supporting the rationale for its therapeutic potential range from reports on in-vitro neuroprotection against Aβ, viruses, and oxidative stress to neuroprotection in rodent models of stroke and hypoxia (see Jul 2002 news story). NAP is thought to modulate the pool of microtubules in neurons, but its exact mechanism of action is not clear. Inhibition of programmed cell death and correction of mitochondrial dysfunction also have been proposed as potential mechanisms.
NAP has been implicated in memory and cognition in mice. Genetic ANAP reduction impairs performance in the Morris water maze, and intranasal dosing with NAP was reported to reverse the effect. In a triple transgenic mouse model of AD, NAP reduced amyloid accumulation and tau hyperphosphorylation and improved performance in the Morris water maze (see Vulih-Shultzman et al., 2007; May 2007 news story; Matsuoka et al., 2008). NAP was reported to rescue a neuronal dysfunction phenotype in a fly model of tauopathy (see Quraishe et al., 2013).
Other preclinical studies have reported beneficial effects of NAP in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) (see Jouroukin et al., 2013; Fleming et al., 2011).
Findings
Four Phase 2 and 3 clinical trials were conducted with a nasal spray formulation of davunetide.
From 2007–2008, a Phase 2 trial compared the effect on memory outcomes of 5 mg once a day, 15 mg twice a day, and placebo in 144 people with aMCI, frequently a prodrome to Alzheimer's disease. This was a four-month, multicenter U.S. study. At conferences, the trial was reported to show a statistically significant improvement in test performance compared with placebo at eight weeks and 16 weeks, but not 12 weeks; a placebo effect was also mentioned. Safety data included headache and nasal irritation, but the drug was generally well-tolerated (see May 2008 news story; company release).
From 2007–2009, a Phase 2 trial compared two different doses of davunetide to placebo in 63 patients with chronic schizophrenia. In this trial, intranasal davunetide missed one coprimary outcome, the MATRICS composite battery of tests, but showed efficacy in the other, the University of California at San Diego performance-based skills assessment, UPSA. The treatment was also reported to show an effect on cortical thickness (see Javitt et al., 2012; Jarskog et al., 2013).
From 2010–2012, a one-year Phase 2/3 trial compared 30 mg of davunetide spray twice a day to placebo in 313 people with the tauopathy progressive supranuclear palsy (PSP). Coprimary outcomes were efficacy as measured by the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL), and safety. The trial included no measures of target engagement. Conducted at 47 sites in North America, Australia, and Europe, this pivotal trial was negative on all endpoints—primary, secondary, and exploratory.
This result halted clinical development of davunetide (see Dec 2012 news story; company press release). It also prompted a halt to recruitment into an ongoing safety and biomarker trial, begun in 2010, of davunetide in frontotemporal lobar degeneration (FTLD) with predicted tau pathology, corticobasal degeneration (CBS), or progressive supranuclear palsy (PSP). Results were formally published (Boxer et al., 2014).
For all clinical trials of Davunetide, see clinicaltrials.gov.
Davunetide was being developed by Allon Therapeutics based in Vancouver, Canada. Allon became insolvent and in July 2013 was acquired by the Canadian pharmaceutical company Paladin Labs (see YahooFinance story).
An intravenous formulation of davunetide exists, as well. Called AL-208, Allon tested this version of the drug between 2006 and 2008 in a Phase 2 trial of the safety and efficacy of a single 300-mg IV dose on cognitive impairment following coronary artery bypass surgery. Conducted in 234 cardiovascular patients, this trial has no published results; however, in a press release, claimed safety and tolerability for AL-208 as seen in a smaller Phase 1 study (see company press release).
Last Updated: 03 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: N/A
Summary
THY-Tau22 mice are a model for tau aggregation, a pathological hallmark of Alzheimer's disease as well as numerous tauopathies. With age these mice develop a variety of tau-related neuropathological changes, including tau hyperphosphorylation, neurofibrillary-like tau inclusions, and ghost tangles. Tau pathology is generally mild at three to four months of age, moderate at six to seven months, and extensive at nine months and beyond.
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
Heterozygous animals develop tau pathology starting at 3-6 months. Pathology becomes more severe and widespread with age. Neurofibrillary tangle-like inclusions occur (Gallyas and MC1+) along with rare ghost tangles and paired helical filament-like structures (Schindowski et al., 2006).
Neuronal Loss
Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).
Gliosis
Age-dependent increase in the number of GFAP+ astrocytes in the hippocampus (hilus, CA1, CA3), cerebral cortex, corpus callosum (Schindowski et al., 2006).
Changes in LTP/LTD
Altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity in 9-10 month old heterozygous animals: PPF increased at 10 ms. Also at this age, impaired maintenance of long term depression as compared with wild-type littermates (Van der Jeugd et al., 2011). Deficit in basal synaptic transmission in the hippocampus, but normal LTP (Schindowski et al., 2006).
Cognitive Impairment
Non-spatial memory affected as early as 6 months; spatial memory impaired only after 9 months (Van der Jeugd et al., 2013). Impaired appetitive responding (Lo et al., 2013).
Last Updated: 25 Nov 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: ITM2B (BRI2)
Mutations: BRI2: Familial Danish Dementia (FDD) duplication
Modification: ITM2B (BRI2): Transgenic
Disease Relevance: Familial Danish Dementia, Cerebral Amyloid Angiopathy, Alzheimer's Disease
Strain Name: N/A
Summary
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease, Traumatic Brain Injury
Strain Name: N/A
Summary
When crossed with R1.40 mice, a YAC-based model that overexpresses APP with the Swedish mutation, no changes in holo-APP or APP C-terminal fragments were observed. The double-cross mice did have significantly higher levels of Aβ40 compared with R1.40 mice with endogenous APOE. No significant differences in Aβ40 levels between APOE4;R1.40 mice, APOE2;R1.40 and APOE4;R1.40 mice (Mann et al., 2004).
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease, Traumatic Brain Injury
Strain Name: N/A
Modification Details
The human APOE3 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 nucleotides of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated.
Other Phenotypes
Intermediate brain APOE and serum cholesterol levels compared with mice with knock-in of APOE4 or APOE2.
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+.
Last Updated: 17 Jul 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease, Traumatic Brain Injury
Strain Name: N/A
Modification Details
The human APOE2 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Nikolaos K. Robakis 
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