Genes: APP, PSEN1
Mutations: APP KM670/671NL, PSEN1: deltaE9
Modification: APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: Fischer 344
Availability: Available through Terrence Town.
TgF344-AD rats express human APP with the Swedish mutation and human PSEN1 with the Δ exon 9 mutation. Both transgenes are driven by the mouse prion promoter (Cohen et al., 2013).
Compared with levels of the endogenous rat proteins, TgF344-AD rats express 2.6 times more human APP and 6.2 times more human PSEN1 in the brain (Cohen et al., 2013). TgF344-AD rats show age-dependent increases in levels of detergent-soluble and detergent-insoluble Aβ40 and Aβ42 between 6 and 26 months; the Aβ42/Aβ40 ratio increases with age in the soluble fraction but decreases in the insoluble fraction (Cohen et al., 2013).
TgF344-AD rats show an age-dependent accumulation of amyloid plaques in hippocampus and cortex between 6 and 26 months of age. Plaques are also detected in the striatum and cerebellum. Cerebral amyloid angiopathy occurs in cortex, hippocampus, striatum, and cerebellum. Plaque-associated neuritic dystrophies are observed (Cohen et al., 2013).
Tau pathology has also been reported in TgF344-AD rats (Cohen et al., 2013). Antibodies directed against specific phospho-tau epitopes (AT8, CP13, pS199/202, pS396) and conformation-selective tau antibodies (MCI and PHF1) stained neurons in hippocampi and cortices of 16-month animals. Silver staining and immunostaining with antibody CP13 revealed neurofibrillary tangle-like structures.
Microgliosis and astrogliosis are apparent by 6 months (Cohen et al., 2013).
Neuron numbers in hippocampus and cortex of TgF344-AD rats are similar to those of wild-type animals at 6 months of age, but by 16 months there is an approximate 40 percent loss of neurons (Cohen et al., 2013).
Hirano bodies and spongiform vacuolar pathology are seen at 16 months (Cohen et al., 2013).
The locus coeruleus may be one of the first brain regions to exhibit tau pathology during the development of AD (Braak et al., 2011), prompting an investigation of locus coeruleus pathology and noradrenergic markers in TgF344-AD rats (Rorabaugh et al., 2017). Hyperphosphorylated tau was detected in the locus coeruleus by 6 months of age, prior to its appearance in medial entorhinal cortex or hippocampus. No neurofibrillary tangles, amyloid plaques, astrogliosis, or neuron loss were seen in the locus coeruleus in animals up to 16 months of age. However, the norepinephrine content in the hippocampus was lower in TgF344-AD rats than in wild-type rats at 16 months, while no differences between the genotypes were seen in the prefrontal cortex at this time.
Network dysfunction, assessed as the coupling between the phase of theta oscillations and the amplitude of gamma oscillations, was recorded in the somatosensory cortices of 9-month transgenic rats (Joo et al., 2017).
When tested at 6, 15, and 24 months, transgenic rats did not show neurologic abnormalities in a screen that included the righting response, eye blink, ear twitch, limb withdrawal in response to tactile stimuli, orienting response to olfactory and visual stimuli, startle response, and visual and tactile placing (Cohen et al., 2013).
Fifteen-month TgF344-AD rats were hyperactive in the open-field test (Cohen et al., 2013). In the elevated plus-maze, 4- to 6-month TgF344-AD rats spent less time in the open arms than did wild-type rats, perhaps indicating increased anxiety (Pentkowski et al., 2018).
Reversal learning in the Morris water maze was impaired in animals as young as 6 months of age (Rorabaugh et al., 2017), and learning deficits in the Barnes maze were reported in 15-month TgF344-AD rats (Cohen et al., 2013).
Deficits in novel object recognition were observed at 24 months (Cohen et al., 2013).
PET imaging showed uptake of the tracer 18F-FDDNP in the frontal cortices of 15-month transgenic rats (Cohen et al., 2013). This tracer binds amyloid plaques and, to a lesser extent, neurofibrillary tangles (Agdeppa et al., 2001).
In a study of male animals, MRI showed differences in structural and functional connectivity between TgF344-AD rats (approximately 6 months of age) and wild-type rats (about 5 months of age) (Munoz-Moreno et al., 2018).
Cerebrovascular dysfunction accompanies vascular amyloid deposition: In cortical penetrating arterioles, normal increases in blood flow in response to hypercapnia were abolished (Joo et al., 2017).
Compared with wild-type rats, TgF344-AD rats showed decreased visual acuity but increased contrast sensitivity at 19 months of age (Tsai et al., 2014).
Pronuclei of Fischer 344 zygotes were co-injected with two cDNAs encoding human APP with the Swedish mutation and PSEN1 with the Δ exon 9 mutation; both genes are driven by the mouse prion promoter (Cohen et al., 2013).
TgF344-AD rats on a Fischer344/NHsd background are available from the Rat Resource & Research Center, Stock# 00699.
SHRSP/FAD. In order to model mixed Alzheimer’s and cerebrovascular pathology, TgF344-AD rats were backcrossed with SHRSP rats. SHRSP/FAD rats manifest chronic hypertension. While placing the AD-linked transgenes on the SHRSP background led to a slight amelioration of plaque pathology, other neuropathological features, including tau pathology, demyelination, and some cerebrovascular changes, were exacerbated compared with the parental lines. The SHRSP/FAD rat model may be suitable for preclinical studies of potential therapies directed against Alzheimer’s disease co-existing with mild cerebrovascular disease. Rats are available through Sally Frautschy.
WKY/FAD. TgF344-AD rats were backcrossed to Wistar Kyoto rats, to place the AD-related transgenes on the same genetic background as the SHRSP/FAD line. Rats are available through Sally Frautschy.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Synaptic Loss
- Changes in LTP/LTD
Age-dependent accumulation of amyloid plaques in hippocampus and cortex between 6 and 26 months of age.
Structures similar in appearance to neurofibrillary tangles revealed by Gallyas staining and immunostaining using an antibody directed against phospo-tau.
Approximate 40 percent loss of neurons in hippocampus and cortex by 16 months.
Microgliosis and astrogliosis are apparent by 6 months.
Changes in LTP/LTD
Deficits in reversal learning in the Morris water maze apparent by 6 months.
Last Updated: 06 Dec 2019
Research Models Citations
- Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, Rakic P, Davtyan H, Agadjanyan MG, Kepe V, Barrio JR, Bannykh S, Szekely CA, Pechnick RN, Town T. A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci. 2013 Apr 10;33(15):6245-56. PubMed.
- Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011 Nov;70(11):960-9. PubMed.
- Rorabaugh JM, Chalermpalanupap T, Botz-Zapp CA, Fu VM, Lembeck NA, Cohen RM, Weinshenker D. Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease. Brain. 2017 Nov 1;140(11):3023-3038. PubMed.
- Joo IL, Lai AY, Bazzigaluppi P, Koletar MM, Dorr A, Brown ME, Thomason LA, Sled JG, McLaurin J, Stefanovic B. Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease. Sci Rep. 2017 Apr 12;7:46427. PubMed.
- Pentkowski NS, Berkowitz LE, Thompson SM, Drake EN, Olguin CR, Clark BJ. Anxiety-like behavior as an early endophenotype in the TgF344-AD rat model of Alzheimer's disease. Neurobiol Aging. 2018 Jan;61:169-176. Epub 2017 Oct 5 PubMed.
- Agdeppa ED, Kepe V, Liu J, Flores-Torres S, Satyamurthy N, Petric A, Cole GM, Small GW, Huang SC, Barrio JR. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer's disease. J Neurosci. 2001 Dec 15;21(24):RC189. PubMed.
- Muñoz-Moreno E, Tudela R, López-Gil X, Soria G. Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease. Alzheimers Res Ther. 2018 Feb 7;10(1):16. PubMed.
- Tsai Y, Lu B, Ljubimov AV, Girman S, Ross-Cisneros FN, Sadun AA, Svendsen CN, Cohen RM, Wang S. Ocular changes in TgF344-AD rat model of Alzheimer's disease. Invest Ophthalmol Vis Sci. 2014 Jan 29;55(1):523-34. PubMed.