Genes: APP, MAPT
Mutations: APP KM670/671NL (Swedish), MAPT P301L
Modification: APP; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: Tg(APPSWE)2576Kha Tg(Prnp-MAPT*P301L)JNPL3Hlmc
Genetic Background: C57BL/6, DBA/2, SJL, SW Mixed Background
Availability: Taconic: Stock# 2469
These mice were made by crossing mice that develop extensive plaque pathology (Tg2576) with a line that develops neurofibrillary tangles (JNPL3). The resulting bigenic mice develop plaque pathology similar to Tg2576 animals, but more extensive neurofibrillary tangles than the JNPL3. The levels of total soluble endogenous and transgenic tau protein and tau mRNA were similar in the brains of bigenic mice and JNPL3 mice (Lewis et al., 2001). Neuropathologically, the mice exhbit a gradual appearance of plaques. By nine months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Astrocytosis and microgliosis are also observed. Behaviorally, the mice exhibit motor disturbances similar to JNPL3, with a comparable range in onset. They also show reduced vocalization and decreased grooming. In addition, progressive hindlimb weakness and a hunched posture have been noted. Eye irritations are also common. Some mice have the Pde6brd1 retinal degeneration mutation which can cause light sensitivity and/or blindness and may affect behavioral testing.
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
Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.
Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).
Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).
Research Models Citations
- Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. PubMed.