Research Models

TMHT (Thy-1 mutated human tau)

Synonyms: TAU 441, hTAU441, TAU441 V337M R406W

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Species: Mouse
Genes: MAPT
Modification: MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A

Neuropathology

Increased total tau and phosphorylated tau species (Thr181, Ser199, Thr231) in the amygdala and hippocampus starting at three months.

Cognition/Behavior

Spatial memory deficits starting at five months by the Morris water maze. Olfactory deficits at five months indicated by the buried food test. No motor deficits (by rotarod, beam walk) or depressive behavior as indicated by the forced swim test.

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+.

Absent

  • Plaques

No Data

Plaques

Absent.

Tangles

Tangles at 4 months and progress with age.

Cognitive Impairment

Cognitive impairment by 5 months as measured by the Morris Water Maze.

Last Updated: 03 Apr 2024

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

mThy1-hAPP751 (TASD41)

Synonyms: Line 41, hAPPSL, hAPP-SL, AβPP751, mThy1-hAβPP751 Swe Lon (line 41), APP751SL, hAPPlon/swe line 41, APP41

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Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: mThy1-hAβPP751 Swe Lon

Summary

These transgenic mice express mutant human APP with both the Swedish (K670N/M671L) and London (V717I) mutations. They develop age-associated amyloid plaques and cognitive 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+.

Absent

  • Tangles
  • Neuronal Loss

No Data

  • Changes in LTP/LTD

Plaques

Plaques start at 3-6 months in the frontal cortex and become widespread with age, affecting the piriform and olfactory cortices, hippocampus, and thalamus (Rockenstein et al., 2001; Havas et al., 2011).

Tangles

Absent.

Neuronal Loss

Absent.

Gliosis

Inflammation related to activated microglia (increased CD11) and reactive astrocytes (increased GFAP) is significant by 6 months and increases with age.

Synaptic Loss

Dystrophic neurites and synaptic loss starting at 12 months.

Changes in LTP/LTD

Unknown.

Cognitive Impairment

Cognitive impairment observed by 6 months by Morris Water Maze (Rockenstein et al., 2005).

Last Updated: 15 Apr 2024

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

J20 (PDGF-APPSw,Ind)

Synonyms: PDGF-hAPP695,751,770V171F, KM670/671NL, hAPPJ20, hAPP, Mucke mice

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Species: Mouse
Genes: APP
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Zbtb20Tg(PDGFB-APPSwInd)20Lms/2Mmjax

Summary

This popular mouse model overexpresses human APP with two mutations linked to familial Alzheimer's disease (the Swedish and Indiana mutations). Transgene expression is driven by the PDGF-β promoter and immunoreactivity is detected in neurons throughout the brain with highest levels in the neocortex and hippocampus.

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+.

Absent

  • Tangles

No Data

Plaques

At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).

Tangles

Absent.

Neuronal Loss

Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

Gliosis

At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

Synaptic Loss

Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).

Changes in LTP/LTD

Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

Cognitive Impairment

Deficits in spatial memory and learning appear as the mice age. By 4 months, J20 mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013) and Morris water maze (Cheng et al., 2007).

Last Updated: 03 Nov 2017

COMMENTS / QUESTIONS

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Further Reading

No Available Further Reading

Therapeutics

Varenicline

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Overview

Name: Varenicline
Synonyms: Champix™, Chantix™, Varenicline tartrate, CP-526,555, Alpha4 beta2 nicotinic receptor agonist
Chemical Name: 7,8,9,10-Tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepin
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pfizer
Approved for: Smoking cessation

Background

Varenicline is a medication approved in the United States and many other countries to aid smoking cessation. It is a partial agonist of the α4β2 subtype of the nicotinic acetylcholine receptor (nAChR). It also acts on α3β4 and α7 nACHRs.  Acting as a partial agonist, varenicline stimulates the α4β2 receptor without producing the full effect of the nicotine ligand.  Its competitive binding on these receptors blocks the ability of nicotine to stimulate the mesolimbic dopamine system, hence its indicated use. Varenicline also acts as an agonist at 5-HT3 serotonine receptors, which are thought to contribute to its mood-altering effects. Side effects of vareniclin include as changes in behavior, agitation, depressed mood, and suicidal ideation, both in people with and without pre-existing psychiatric conditions. Vareniclin is one of several α4β2 nACHRs agonists that have been tested as treatments for Alzheimer's disease.

Findings

In 2009 and 2010, Pfizer compared varenicline to placebo in a six-week Phase 2 trial in 66 patients with mild to moderate Alzheimer's disease for its ability to improve cognition as measured by the ADAS-Cog. The multicenter trial was conducted in South Korea. The trial assessed varenicline's safety, tolerability, and ability to improve cognition as measured by the ADAS-Cog. Fifty-four people completed the trial. Varenicline did not improve cognition, nor did it have a benefit on most of the study's secondary outcomes. It did, however, worsen participants' neuropsychriatic state and caused gastrointestinal side effects. Development of varenicline for Alzheimer's therapy was discontinued in 2011. For results of this trial see clinicaltrials.gov.

Last Updated: 11 Jan 2016

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Further Reading

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