Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Transgene consisting of the signal plus 99-amino acid carboxyl-terminal sequence (SbC) of human APP under the control of a cytomegalovirus enhancer/β-actin promoter.
Last Updated: 25 Nov 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, RAGE (AGER)
Modification: APP: Transgenic; RAGE (AGER): Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Neuropathology
Significantly increased activation of microglia and astrocytes compared to mice expressing mutant APP alone.
Cognition/Behavior
Tg-mAPP/RAGE mice display abnormalities in spatial learning and memory at age three to four months of age, whereas deficits occur later in mice expressing mutant APP alone and are less severe.
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, RAGE (AGER)
Modification: APP: Transgenic; RAGE (AGER): Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Neuropathology
Bigenic mice expressing dominant-negative RAGE as well as mutant APP displayed diminished neuropathology compared with mice expressing mutant APP alone, including the area occupied by acetylcholinesterase-positive fibers in the subiculum at three to four and 14 to 18 months of age (Arancio et al., 2004).
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APOE
Modification: APOE: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: APOE
Modification: APOE: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Modification Details
Last Updated: 06 Mar 2018
Further Reading
No Available Further Reading
Overview
Name: Pioglitazone
Synonyms: AD4833, Actos®, Glustin™, Piozone®
Chemical Name: 2,4-Thiazolidinedione
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Mild Cognitive Impairment
U.S. FDA Status: Mild Cognitive Impairment (Phase 3)
Company: Takeda Pharmaceutical Company, Zinfandel Pharmaceuticals Inc.
Approved for: Type 2 diabetes mellitus
Background
Pioglitazone is an insulin sensitizer of the thiazolidinedione class of peroxisome-proliferator activated receptor γ (PPARγ) agonists. Takeda developed pioglitazone as a once-daily treatment of type 2 diabetes. The FDA approved it in 1999 as an adjunct to diet and exercise for the control of blood sugar in adults with this disease. Since then pioglitazone has come to be prescribed worldwide, but was withdrawn from the market in Germany and France because of concerns that it might increase the risk of bladder cancer. The issue remains under review in the United States, though in its update issued in August 2013, the FDA did not conclude that pioglitazone increased the risk of bladder cancer. Generic tablet versions became available starting in 2012.
In recent years, PPARγ has come to be a target of interest for Alzheimer's drug development, both because of a general overlap of metabolic disease and Alzheimer's disease risk factors and because cell-based and animal studies have implicated PPARγ, in particular, to play a role in neuroinflammatory processes in Alzheimer's and other neurodegenerative conditions. For example, PPARγ activation has been shown to modulate the microglial response to amyloid deposition in such a way that it increases Aβ phagocytosis and decreases cytokine release (Dec 2012 news story; Yamanaka et al., 2012; Mandrekar-Colucci et al., 2012).
Findings
From 2002 to 2005, a Phase 2 study sponsored by the National Institute on Aging evaluated the safety and tolerability of pioglitazone in patients with AD and gathered pilot data on whether this drug might affect measures of cognition, daily function, and behavior. Twenty-nine patients with mild to moderate AD but without diabetes took up to 45 mg per day of pioglitazone or placebo for 18 months. Consistent with the known side effects of pioglitazone, about a fourth of participants developed peripheral edema; other than that they tolerated the drug well. No indications for a clinical benefit arose from this trial (see Geldmacher et al., 2011; Sep 2010 news story).
A Japanese open-label study of 42 patients who had both mild Alzheimer's and diabetes suggested a benefit for both diseases after six months of treatment with 15 to 30 mg/day of pioglitazone, as did a previous pilot study in patients who had mild AD or mild cognitive impairment and diabetes (Sato et al., 2011; Hanyu et al., 2009).
In 2012, Takeda conducted a Phase I trial in the United States to evaluate the effects of two weeks of pioglitazone treatment on blood flow in brain areas important for cognition in 61 healthy older participants (NCT01456117). Results are unpublished.
In 2013-2015, Takeda and Zinfandel Pharmaceuticals conducted "TOMMORROW," a Phase 3 trial that enrolled 3,494 cognitively normal participants in the United States, Australia, Europe, and the U.K. This study was unusual in that it had two separate goals. One was to evaluate how accurately a diagnostic algorithm based on the genes ApoE and TOMM40, developed by Zinfandel, predicts a person's risk of developing mild cognitive impairment due to AD (MCI-AD) within five years. The other was to evaluate pioglitazone's ability to delay this diagnosis in people deemed high-risk by the diagnostic assay. The assay is being co-developed as a companion diagnostic for preventive treatment. Participants at high risk of developing MCI-AD according to the diagnostic algorithm were randomized to pioglitazone or placebo; participants at low risk received placebo. The primary endpoint for the diagnostic assay was the time to diagnosis for placebo-treated participants in the low-risk group compared with the high-risk group; the primary endpoint for pioglitazone was the time to diagnosis for pioglitazone-treated versus placebo-treated participants in the high-risk group. This trial used 0.8 mg pioglitazone per day, a lower dose than is used to treat diabetes (Moon et al., 2011). Approximately 300 high-risk participants will enter an amyloid-related imaging abnormalities (ARIA) substudy. Each participant was to take a tablet—pioglitazone or placebo—once daily for five years, visit his or her study clinic 14 times, and take a telephone call three months after each visit for a follow-up assessment (Aug 2013 conference story). Approximately 300 high-risk participants entered an ARIA substudy at the request of the FDA. This was later changed to volumetric MRI, on the understanding that low-dose pioglitazone was unlikely to affect brain amyloid.
In early 2018, TOMMORROW was terminated after failing a futility analysis (Jan 2018 news). According to published trial results, pioglitazone did not delay the onset of MCI, after a mean treatment time of about two years. The diagnostic algorithm produced a three-times enrichment of events in the high-risk placebo group compared to the low-risk placebo group, but did not reach a prespecified significance threshold (Burns et al., 2021). The treatment did not alter the rate of change of brain volumes on MRI.
For trials of pioglitazone in Alzheimer's disease, see clinicaltrials.gov.
In addition, pioglitazone was evaluated in a Phase 1 study in patients with multiple sclerosis, but development for this indication stopped.
Clinical Trial Timeline
- Phase 2
- Phase 3
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| Takeda Pharmaceutical Company |
NCT00982202 |
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| Takeda Pharmaceutical Company |
NCT01931566 |
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Last Updated: 05 Jan 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.D2-Tg(Thy1-APPSwe)71Blt; B6.D2-Tg(Thy1-APPSwe)72Blt
Neuropathology
Amyloid plaques by 17-18 months in the neocortex and hippocampus with detection of five to ten-fold more Aβ40 than Aβ42. Plaque burden significantly lower than in the double transgenic PS2APP. Lower levels of insoluble Aβ40 and Aβ42 than the PS2APP mouse at 16-18 months (Richards et al., 2003).
Cognition/Behavior
Unknown.
Last Updated: 06 Apr 2022
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, MAPT, PSEN2
Modification: APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.D2-Tg(Thy1-APPSwe, Prp-PSEN2N141I, Thy1-TauP301L)
Summary
These triple transgenic mice express mutant APP, PSEN2, and MAPT. They show age-dependent accumulation of Aβ plaques and neurofibrillary tangle-like pathology, starting around four months of age (Grueninger et al., 2010).
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
Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).
Tangles
Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).
Neuronal Loss
No overt neuronal loss in the hippocampus at 16 months (Grueninger et al., 2010).
Cognitive Impairment
Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).
Last Updated: 07 Apr 2022
Further Reading
No Available Further Reading
Overview
Name: MK-7622
Therapy Type: Small Molecule (timeline)
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Merck
Background
Merck is developing MK-7622 as an add-on therapy to the cholinesterase inhibitor donepezil for the treatment of Alzheimer's disease. No studies have been published on this compound in the peer-reviewed literature or other publicly available documents. Merck has published on its preclinical research in mice and rhesus monkeys of allosteric M1 muscarinic agonists, which would enhance the effect of acetylcholine neurotransmission and could be suitable as adjunct therapy to cholinesterase inhibitors (see Aug 2009 news; Uslaner et al., 2012; Lange et al 2015). MK-7622 appears to have grown out of this program.
Findings
No information about Phase 1 clinical studies of MK-7622 is available in the public domain. In October 2013, Merck began a Phase 2 trial in the United States to evaluate the compound's tolerability and efficacy as a symptomatic adjunct to donepezil therapy in patients with probable AD as diagnosed by two conventional diagnostic criteria, the NINCDS-ADRDA and DSM-IV.
This multicenter trial was to use two stages to compare three doses of MK-7622, given once daily as capsules. Stage 1 randomized participants to receive either placebo or 45 mg of MK-7622 for six months, and interim analysis was to determine if the trial proceeds to Stage 2. Stage 2 was to randomize a separate group of participants to receive either placebo or 5, 15, or 45 mg of MK-7622 for six months. The primary outcome measures were change from baseline in the ADAS-Cog11 at three months, the number of patients who have an adverse event, and the number of patients who drop out of the trial. This trial does not employ biomarkers.
This trial was set to enroll 830 patients and run until 2020; however, in March 2016, it stopped recruiting and in April it was terminated at 240 participants. Accessed November 2016, Merck's Phase 2 and 3 development pipeline no longer listed MK-7622. No study results were published, or posted on Merck's website.
For clinical trials with this compound, see clinicaltrials.gov.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
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| Merck |
NCT01852110 |
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Last Updated: 02 Dec 2016
Further Reading
No Available Further Reading
Species: Mouse
Modification: Spontaneous
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Last Updated: 25 Nov 2019
Further Reading
No Available Further Reading
Hiroshi Mori 
COMMENTS / QUESTIONS
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