Table 1 Summary of 8 commonly used AD transgenic mouse models

Tg2576

hAPP 695

Dense plaque (7–8 mo); major plaque deposition (11–13 mo) on parenchyma and vascular structures

Female: more plaques and congnitive impairment. Decreased REM sleep and delayed sleep onset (22 mo). Male: more aggressive. Disruped sleep EEG rhythms (22 mo).

Impairment of spatial and working memory (9–12 mo). Electrically evoked seizure (12–14 mo). Decrease of frequency of burrowing prior amyloid plaques (3 mo).

High lethality in certain genetic background. Lack of tau pathology.

[8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]

TgCRND8

Double mutant: hAPP 695 (KM670/671 NL and V717F)

Aβ40 levels stabilized and Aβ42 increased (4–10 weeks). Amyloid deposition in the cerebral cortex (2–3 mo). Dense-cored plaques and neuritic pathology in the hippocampus, midbrain, brainstem and cerebellum (4–5 mo). Metabolic impairment, reduced NAA levels in hippocampus and cortex (2–3 mo) and dysregulation of myo-inositol levels througout mice aging.

Females: earlier learning and memory deficits (4 mo); Male: reduced REM and NREM sleeps (3–8 mo), and decreased NREM sleep (11 mo); Compensated for stereotypic behaviors (5 mo).

Disrupt in sleep cycle. Metabolic disturbance.

Aggressive model. Lack of tau pathology. Shortened life span.

[27, 30,31,32,33,34,35,36,37,38,39,40,41]

PS19

hMAPT (P301S) - mixed background

Tau seeding (1.5 mo). NFTs (6 mo). Neurodegeneration begins in hippocampus and entorhinal cortex (9 mo).

Female: higher survival rate

Impairment in memory and learning, limb weakness, hyperactivity (3 mo). Paralysis (7 mo)

No amyloid pathology. Shortened life span.

[42,43,44,45]

hMAPT (P301S) - congenic background

NFTs (6 mo). Median lifespan of 11–15 mo.

N/A

Hyperactivity (3 mo). Altered pain perception and startle response (3 mo).

Less variability in pathologenesis compared to mixed background

[45,46,47,48]

rTg4510

hMAPT P301L crossed with a tTA allele

Pre-tangles develop (2.5 mo). Argryophilic tangle-like inclusions (4–5.5 mo). Robust tau hyperphosphorylation, neuronal loss and tangle formation (5.5 mo)

Female: more hyperphosphorylated tau, but not for tau transgene expression. Worsened deterioration of spatial learning and memory

Decline in spatial memory function (4 mo). Hyperactivity and increased anxiety (7 mo)

Pathology restricted to the cortex and hippocampus. Robust tau expression and neurodegeneration. endogenouse mouse gene disruption

[49,50,51,52,53,54,55,56,57]

P301L

Human 4R/2N introduced to P301L mutation

NFTs without axonal dilations in brainstem and spinal cord (6 mo). Lifespan of 8–12 mo.

N/A

Impairments in passive avoidance test (5 mo) and object recognition test (9 mo). Motor deficits (7 mo).

Of younger mice, P301L mice may have better cognitive abilities compared to wt controls.

[58,59,60]

APP/PS1

Double mutant: hAPP695 (KM670/671 NL) and PS1 (delEx9)

Aβ deposits, microglial and astrocytic activation (4 mo). Amyloid plaques in hippocampus and cortex (9 mo). Modest neuronal loss adjacent to amyloid plaques and synaptic dysfunction (8–10 mo). Increase in Aβ40 and Aβ42 in hippocampal regions of Nrf2 KO mice and increase in microglial activation and an accumulation of endosomes and lysosomes.

No apparent differences reported in cognitive deficits.

Memory deficits (6 mo); Deficits in spatial navigation and learning (12 mo). Nest-building and burrowing (8–14 mo).

Lack of tau pathology. LTP impairment (8–10 mo) but no PPF deficits (8–9 mo). Hippocampal neuronal circuit dysfunction.

[61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77]

5xFAD

Five mutations: Human Swedish, London, Florida APP mutations in APP and M146L and L286V in PS1 genes - Tg6799, Tg 7092, Tg 7031

Amyloid aggregates (1.5 mo). Amyloid plaques (2 mo) in hippocampus and cortex. Neuroinflammation phenotypes with atrogliosis and microgliosis (2 mo). Progressive neuonral loss (6 mo). Dystrophic neurites plateued (8–12 mo). High vs medium vs low expression

Female: more severe amyloid pathology. Male more significantly reduced PPF nad decreases in HDL levels.

Impaired spatial memory (4 mo). Motor impairments (9 mo). Reduced anxiety, increased hyperactivity (12 mo)

LTP deficits (12 mo). Lack of tau pathology. Molecular signatures are well aligned with human AD brains.

[78,79,80,81,82,83,84,85,86]

5xFAD (C57BL6)

Amyloid plaques in subiculum and layer V pyramidal neurons (16 days). Intraneuronal plaques (6 weeks). Plaques in cortex, hippocampus, thalamus (2 mo) and spinal cord (3 mo). Thinner myelin sheathes (1 mo) and shorter axon calibers (2–3 mo). Loss of 40% of layer V pyramidal neurons (12 mo).

N/A

Impaired memory in cross-maze test and reduced anxiety in elevated plus maze (3–6 mo).

Lack of tau pathology. Aggressive onset of amyloid pathology.

[87,88,89]

5xFAD (AD-BXD)

Varying amyloid pathology and cognitive impairment, which did not correlate.

No difference in amyloid pathology or transgene expression. Females demonstrated more motor impairments compared to males.

Varying behavior and cognitive function. Impaired function due to age and existence of transgene.

Used to model the genetic variation in humans and to identify transcriptional networks protective against AD-related cognitive decline.

[90]

3xTg-AD

Triple mutant: hPS1 (M146V), hAPP (KM670/671 NL), and MAPT P301L

Extraceullular amyloid deposits in frontal cortext (6 mo); Plaques in hippocampus (12 mo). Aggregates of conformationally-altered and hyper-phosphorylated tau in hippocampus (12–15 mo).

Female: earlier development of plaques and tangles (12 -18 mo) associated with pronounced cognitive decline, and significant age-dependent increases in microglial activation. Male mice: Markers of neuroendocrine aging appeared earlier and increased morbidity/mortality rates.

Impairment with spatial learning and memory deficits (6 mo). Age depedent cognitive decline noticed at 6, 12, and 20 mo.

Intraneuronal Aβ immunoreactivity (3–4 mo). Lack of neuronal loss. Genetic drift observed within this model.

[9, 91,92,93,94,95,96]