Species: Rat
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
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
Neurofibrillary tangles, demonstrated by Gallyas silver stain, are present in the brainstem and spinal cord.
Neuronal Loss
Although neuron loss has not been documented, chromatolytic neurons and damaged axons were seen in the brains of 7-month animals, particularly in the brainstem reticular formation.
Gliosis
Astrogliosis and microgliosis are present in brainstem regions bearing neurofibrillary tangles.
Cognitive Impairment
Sensorimotor deficits and abnormal reflexes observed as early as 3 months, but no data available from cognitive tests.
Last Updated: 07 Jun 2019
Further Reading
No Available Further Reading
Species: Rat
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
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
Argyrophilic neurofibrillary tangles accumulate in cortex, hippocampus, thalamus, and brainstem.
Synaptic Loss
Decreased levels of synaptophysin and a decreased number of synaptic vesicles per synapse in animals at the end of the lifespan of this line.
Neuronal Loss
No neuron loss was observed in the hippocampi or cortices of male rats examined at 15 month of age.
Cognitive Impairment
Sensorimotor deficits and abnormal reflexes observed as early as 3.5 months, but no data available from cognitive tests.
Last Updated: 07 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Virus
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, 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+.
Neuronal Loss
Neuron loss in cortex, seen at 3 months.
Gliosis
Astrogliosis, but not microgliosis, seen at 3 months.
Cognitive Impairment
Deficits in contextual and cued fear conditioning, seen at 3 months.
Last Updated: 05 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Virus
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: N/A
Summary
To create this model, an adeno-associated viral (AAV) vector encoding human tau with the P301L mutation was injected into the ventricles of neonatal mice. At 6 months of age, TauP301L-AAV mice exhibit neurofibrillary tangles, gliosis, and behavioral deficits, but no cortical neuron loss.
Unless specified otherwise, the description on this page refers to 6-month-old mice.
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
Argyrophilic, Thioflavin S-positive neurofibrillary tangles in cortex and hippocampus.
Synaptic Loss
The accumulation of a PSD95 fragment suggests the possibility of synaptic abnormalities, although synaptic structure and function have not been assessed directly.
Neuronal Loss
No cortical neuron loss at 6 months.
Gliosis
Astrogliosis and microgliosis observed at 3 months.
Cognitive Impairment
Deficits in cued and contextual fear conditioning observed at 6 months.
Last Updated: 05 Jun 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, PSEN1
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax
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+.
Plaques
Amyloid plaques observed in hippocampus, cortex, thalamus, and spinal cord. Amyloidosis more severe in females than males.
Synaptic Loss
Spine density was reduced in pyramidal neurons in somatosensory and prefrontal cortices, but not in the hippocampi, of 5xFAD mice crossed with mice expressing yellow fluorescent protein (YFP mice), compared with mice expressing YFP alone.
Neuronal Loss
Approximate 40 percent loss of layer V pyramidal neurons at one year.
Gliosis
Microgliosis and astrogliosis are associated with amyloid plaques; microgliosis is associated with vascular damage.
Changes in LTP/LTD
LTD was induced in layer V cortical neurons of 8- to 10-week-old 5xFAD mice using the same protocol that induced spike-timing-dependent LTP in neurons of non-transgenic mice. LTP at Schaffer collateral-CA1 synapses was decreased in 5xFAD by 4 months of age.
Cognitive Impairment
Impairments of spatial working memory and reduced anxiety emerge between 3 and 6 months and worsen with age.
Last Updated: 30 Jan 2025
Further Reading
No Available Further Reading
Overview
Name: DNL747
Synonyms: SAR443060
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Inactive), Amyotrophic Lateral Sclerosis (Inactive)
Company: Denali Therapeutics Inc., Sanofi
Background
DNL747 is a brain-penetrant, small-molecule inhibitor of RIPK1, i.e., receptor-interacting serine/threonine-protein kinase 1. Originally developed in the laboratory of Junying Yuan at Harvard Medical School, the compound was licensed to Denali Therapeutics, which has partnered with Sanofi to develop it for the treatment of AD, ALS, and MS.
RIPK1 forms a signaling hub downstream of the TNF receptor pathway, which regulates inflammation. RIPK1 has been shown to initiate both necroptosis and apoptosis (Vandenabeele et al., 2010; Caccamo et al., 2017; Amin et al., 2018).
RIPK1 mediates disease-associated microglial activation and pro-inflammatory cytokine release in Alzheimer’s (Ofengeim et al., 2017). The kinase is located in the molecular pathogenic pathway of ALS/FTD caused by mutations in the endogenous RIPK1 suppressors optineurin and TBK1, and has been reported to regulate progranulin expression (Ito et al., 2016; Xu et al., 2018; Mason et al., 2017). RIPK1 has also been implicated in necroptosis in multiple sclerosis (Ofengeim et al., 2015). This and other work have raised the profile of RIPK1 as a glial target to try to reduce neuroinflammation and cell death across several neurodegenerative diseases (Yuan et al., 2019).
No preclinical studies on DNL747 are published in a peer-reviewed journal. Some efficacy data from human primary cells and 5xFAD and SOD1 mouse models, and safety results from toxicity studies in rats and cynomolgus monkeys, are publicly available as part of the company’s November 2017 filing with the Securities and Exchange Commission (pp 129-131 on sec.gov).
Findings
In March 2018, Denali started evaluating single and multiple doses of DNL747 in 56 healthy volunteers in the Netherlands. In November that year, the company announced that DNL747 was generally well-tolerated at doses that met goals for brain exposure and target engagement as measured by a blood-based biomarker of RIPK1 activity (see company press release).
In December 2018, Denali started a single-site, Phase 1 study of DNL747 in 16 people with ALS, also in the Netherlands. This crossover trial randomized participants to either DNL747 or placebo for 29 days and, after 14 days of washout, switched drug/placebo assignment in a second 29-day treatment period. Primary outcomes measured safety and tolerability, secondary outcomes measured pharmacokinetics and -dynamics by day 86.
In February 2019, a Phase 1 trial at three centers, in Florida and the Netherlands, began enrolling 16 people with an Alzheimer’s diagnosis supported by biomarker evidence of amyloid positivity. This trial used the same 29-day crossover design and outcome measures and was completed in December 2019.
On June 9, 2020, the company announced it was pausing further clinical development of DNL747 in favor of its successor compound, DNL788. Both Phase 1 trials, for ALS and AD, had shown DNL747 to have been safe and well-tolerated at the doses given. However, target receptor occupancy data indicated that higher doses would be needed to achieve therapeutic efficacy, and separate chronic toxicity studies in cynomolgus monkeys indicated potential safety risks of increasing dose (see press release). Phase 1 data was published after peer review (Vissers et al., 2022).
For trials of this compounds, see clinicaltrials.gov
Last Updated: 09 Feb 2023
Further Reading
No Available Further Reading
Species: Rat
Genes: APP, PSEN1
Modification: APP: Virus; PSEN1: Virus
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Adeno-associated viral (AAV) vectors separately encoding human APP with the Swedish and London mutations and human PSEN1 with the M146L mutation were injected bilaterally into the hippocampi of young adult (8-week-old) rats. AAV-AD rats develop amyloid plaques and cerebral amyloid angiopathy, accrue hyperphosphorylated tau, and exhibit progressive behavioral impairments.
Only male rats were used in the study reported here. Controls rats were injected with only with AAV carrying M146L PSEN1.
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
Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection.
Tangles
Immunostaining with monoclonal antibodies AT8 and AT100 suggests the presence of (pre)tangle-like structures 30 months post-injection.
Gliosis
No astrogliosis observed up to 30 months post-injection.
Changes in LTP/LTD
Deficits in LTP as Schaffer collateral-CA1 synapse at 10 months (8 months post-injection). LTD similar to controls.
Cognitive Impairment
AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training.
Last Updated: 22 Feb 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: Bace1
Modification: Bace1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
These transgenic mice were designed to mimic BACE1 inhibition, while avoiding the developmental effects of Bace1 deficiency that are seen in germline knock-outs. They were generated by crossing mice with a floxed Bace1 gene to mice carrying a transgene encoding Cre recombinase fused to the estrogen receptor, inserted at the ROSA26 locus. Upon administration of tamoxifen, Bace1 expression is abolished throughout the body. In the mice described here, tamoxifen was administered at 3 months of age. (Hereafter, these mice are referred to as “BACE1-deficient mice.”)
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+.
Changes in LTP/LTD
LTP at Schaffer collateral–CA1 synapses was similar in slices obtained from 12-month BACE1-deficient and control mice.
Cognitive Impairment
Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning when tested at 9 months of age.
Last Updated: 22 Feb 2019
Further Reading
No Available Further Reading
Species: Mouse
Genes: Bace1
Modification: Bace1: Conditional Knock-out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
In these conditional knock-out mice, Bace1 expression is eliminated in forebrain excitatory neurons beginning during the first postnatal week. These mice were generated by crossing mice with a floxed Bace1 gene to mice carrying a transgene encoding Cre recombinase driven by the CamKIIα promoter (hereafter, these crosses are referred to as “BACE1-deficient mice”).
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+.
Cognitive Impairment
Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning.
Last Updated: 22 Feb 2019
Further Reading
No Available Further Reading
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