Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease
Strain Name: B6.Cg-Tg(Thy-MAPT*)2652Gds
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
Absence of mature neurofibrillary tangles, but extensive pretangle pathology throughout the brain (e.g. phospho-tau).
Cognitive Impairment
Deficits in spatial learning and memory as indicated by performance in the Barnes maze at multiple time points (3, 6, 11 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
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
Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).
Synaptic Loss
Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.
Changes in LTP/LTD
Impaired hippocampal LTP in the CA1 and CA3 areas.
Cognitive Impairment
Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.
Last Updated: 14 Oct 2016
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP
Modification: APP: 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+.
Plaques
Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.
Tangles
Tangles are not observed, but hyperphosphorylated tau develops with age.
Neuronal Loss
Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).
Gliosis
rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.
Cognitive Impairment
No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).
Last Updated: 13 Apr 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 APP transgenic overexpresses mutant human APP under the control of the Thy-1.2 promoter, driving neuronal expression. The transgene carries two mutations associated with familial Alzheimer’s disease: the Swedish double mutation (K670N/M671L) and the Austrian mutation (T714I). The expression level of human APP was reported as approximately 1.4-fold endogenous APP (Yamada et al., 2009).
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
These mice develop progressive amyloid deposition in the cerebral cortex by 9-12 months. By 21 months of age amyloid pathology is extensive.
Last Updated: 06 Apr 2022
Further Reading
No Available Further Reading
Overview
Name: Allopregnanolone
Synonyms: brexanolone, 3α-hydroxy-5α-pregnan-20-one, 3α,5α-tetrahydroprogesterone
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Status in Select Countries: Approved for postpartum depression
Background
Allopregnanolone is a neurosteroid metabolite of progesterone. It is an allosteric modulator of inhibitory γ-aminobutyric acid (GABA-A) receptors on neural stem cells and other cell types in the brain (Luchetti et al., 2011). Allopregnanolone levels have been reported to be reduced in the temporal cortices of people with Alzheimer's disease (Naylor et al., 2010).
In transgenic Alzheimer's mouse models, allopregnanolone has been reported to increase neurogenesis, reduce amyloid deposition, and improve performance on learning and memory tests (e.g., Wang et al., 2010; Chen et al., 2011; Zhang et al., 2015). The drug also has been proposed to promote neuron and oligodendrocyte maturation and improve mitochondrial function in AD mice (Chen et al., 2020; Wang et al., 2020). In mouse models of the lipid storage disease Niemann-Pick Type C, restoring low allopregnanolone levels lengthened survival, a neuroprotective effect thought to be mediated by the pregnane X steroid receptor (Sep 2006 news).
The rationale behind evaluating allopregnanolone in Alzheimer's is that a combined regenerative and neuroprotective effect may counteract ongoing neuronal cell loss in this neurodegenerative disease (Brinton and Wang, 2006; Brinton, 2013; Irwin et al., 2014). However, other studies have reported that allopregnanolone can impair learning function in two different AD mouse strains (e.g., Bengtsson et al., 2013). Newer data indicate that continuous elevation of allopregnanolone in mice worsens amyloid load and learning, while intermittent dosing has opposite, beneficial effects (Bengtsson et al., 2020).
Findings
From August 2014 to February 2018, an NIH-funded Phase 1 study compared 2, 4, and 6 up to 18 mg of allopregnanolone to placebo, all infused once a week for three months. Conducted at the University of Southern California, the study enrolled 24 men and women with a clinical diagnosis of MCI due to AD or mild AD; 18 received allopregnanolone and 6, placebo. Primary outcome measures include various safety parameters including brain MRI; secondary outcomes are pharmacokinetics, cognitive batteries, and structural and functional MRI. Both drug and placebo were being manufactured at the University of California, Davis (see Dec 2014 conference news; Aug 2013 conference news).
According to trial results presented at the 2018 CTAD meeting, the 2, 4, and 6 mg doses produced no adverse events or amyloid-related imaging abnormalities on MRI, and clinical results remained in the normal range. The drug caused sleepiness at 10 mg in women and 6 mg in men. Treatment was associated with less atrophy of the left hippocampus compared to placebo, more so in APOE4 carriers. The 4 and 6 mg doses improved functional connectivity in some brain regions. Exploratory cognitive measures found high variability and no significant differences between drug and placebo groups (Nov 2018 conference news). Results were published (Hernandez et al., 2020). Additional analysis of exploratory imaging data indicated that allo treatment improved white matter integrity and functional connectivity in some brain regions (Raikes et al., 2022). Data presented at the October 2023 CTAD conference showed slowing or reversing of hippocampal atrophy in ApoE4 carriers with amyloid pathology and loss of hippocampal volume at the start of the study.
In October 2019, a Phase 1 dose-finding study at the University of Southern California began testing intramuscular injections of allopregnanolone in lieu of infusions. The trial is enrolling 12 people with MCI due to AD or mild AD to receive 4 to 18 mg of drug weekly for up to four weeks, with pharmacokinetic analysis to determine the equivalent dose to the 4 mg infusion. Participants will continue that dose for a total of 12 weeks. Endpoints are safety, pharmacokinetics, patient satisfaction, and feasibility. Other outcomes include MRI measures of brain volume, standard tests of cognition, daily function, sleep quality, and physical activity. The trial was slated to finish in June 2023.
A 200-participant Phase 2 trial began in August 2023. Participants have probable AD and carry an ApoE4 allele, but the trial requires no biomarker confirmation of Alzheimer's as underlying etiology. Participants will be randomized to 4 mg allopregnanolone or placebo infusion once weekly for 12 months, followed by a six-month, open-label extension. The primary outcome is hippocampal volume. Secondary outcomes include measures of cognition and function, safety, and tolerability. Blood markers, various MRI modalities, as well as clinical measures will serve as exploratory outcomes.
Allopregnanolone is also being evaluated in traumatic brain injury, as well as post-traumatic stress, depression, anxiety disorders, Tourette syndrome, and tinnitus.
For all trials of allopregnanolone, see clinicaltrials.gov.
Last Updated: 19 Dec 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: APP, PSEN1
Modification: APP: Transgenic; PSEN1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Tg(Thy1-APP)3Somm/J; Psen1tm1.1Tcs
This mouse model is a cross between a well-characterized APP transgenic (APP23) and a PSEN1 knock-in mouse (PS1-R278I) that expresses human PSEN1 with a mutation linked to atypical AD. The R278I mutation alters γ-secretase processing of APP, leading to unusually high levels Aβ43 with correspondingly low levels of Aβ40 due to impaired trimming of the Aβ43 peptide (Nakaya et al., 2005).
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
By 6 months of age amyloid plaques accumulate in the cortex and hippocampus. A high percentage of plaques are thioflavin-S –positive cored plaques.
Gliosis
Astrocytosis in the vicinity of plaques in the hippocampus and cortex by 9 months.
Cognitive Impairment
Short-term memory deficits are apparent by 3 to 4 months as measured by the Y maze.
Last Updated: 08 Mar 2018
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Pick's disease, Alzheimer's Disease
Strain Name: N/A
Summary
This transgenic mouse is rare among tauopathy models because it was engineered to overexpress mutant tau with three microtubule binding repeat domains (3R tau), rather than four domains (4R tau). The transgene includes two mutations associated with familial Pick’s disease, L266V and G272V, and like human mutation carriers, the mice develop neuronal tau inclusions described as Pick bodies. The mice also develop age-related neurodegeneration in the hippocampus and cortex as well as behavioral deficits indicative of cognitive and motor impairment.
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
Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.
Synaptic Loss
Synapto-dendritic damage manifested as reduced dendritic density, reduced MAP2 immunoreactivity, and accumulation of 3R tau in dendrites.
Neuronal Loss
Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.
Gliosis
Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.
Cognitive Impairment
By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.
Last Updated: 25 Nov 2019
Further Reading
No Available Further Reading
Martin Rossor 
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