Background
Matching your model to your experimental question - what is it that you want to study?
Amyloid plaques and CAA
Model | Transgene | Transgenic promoter | Availability | Reference |
---|---|---|---|---|
APP Transgenics
| ||||
PDAPP | huAPP770 (Ind) minigene (cDNA + introns 6–8) |
PDGFB
| Novartis | [2] |
Tg2576 | huAPP695 (Swe) | hamster Prnp
| Taconic, Charles River | [95] |
C3–3 | mo/huAPP695 (Swe) | mouse Prnp
| MMRRC 34828-JAX | [96] |
APP23 | huAPP751 (Swe) | mouse Thy1
| JAX 030504 | [100] |
J20 | huAPP770 (Swe/Ind) minigene (cDNA + introns 6–8) |
PDGFB
| MMRRC 34836-JAX | [54] |
TgCRND8 | huAPP695 (Swe/Ind) | hamster Prnp
| Peter St. George-Hyslop | [51] |
Tg-SwDI | huAPP770 (Swe/Dutch/Iowa) | mouse Thy1
| MMRRC 34843-JAX | [210] |
APP/PS1 Transgenics
| ||||
APP/PS1 Line 85 | mo/huAPP695 (Swe); Tg huPSEN1 (ΔE9) | mouse Prnp
| MMRRC 34832-JAX, 34,829-JAX | [99] |
APPPS1 | huAPP695 (Swe); huPSEN1 (L166P) | mouse Thy1
| Mathias Jucker | [211] |
5XFAD Tg6799 | huAPP695 (Swe/Flo/Lon); huPSEN1 (M146 L/L286 V) | mouse Thy1.2
| MMRRC 34840-JAX, 34,848-JAX | [47] |
Tau Transgenics
| ||||
Tau Tg Line 43 | huMAPT3R0N (wt) | mouse Prnp
| JAX 003741 | [212] |
JNPL3 | huMAPT4R0N (P301L) | mouse Prnp
| Taconic | [34] |
hTau.P301S | huMAPT4R0N (P301S) | mouse Thy1.2
| Michel Goedert | [213] |
PS19 | huMAPT4R1N (P301S) | mouse Prnp
| JAX 008169 | [33] |
APP/PS1/Tau Transgenic
| ||||
3xTg-AD | huAPP695 (Swe); MAPT4R0N (P301L); Psen1
M146V knock-in | mouse Thy1.2
| MMRRC 34830-JAX | [101] |
Model | Allele | Targeting approach | Availability | Reference |
---|---|---|---|---|
APPNLh
| endogenous mouse App with Swe mutation and humanized Aβ domain | Knock-in | NA | [89] |
APP R1.40 | complete human genomic APP (Swe) | YAC transgenic | MMRRC 34831-JAX | [86] |
APPSL
| mouse/human App hybrid with humanized Aβ domain (Swe/Lon) | Knock-in | NA | [92] |
APPDSL
| endogenous mouse App with humanized Aβ domain (Swe/Dutch/Lon) | Knock-in | Hui Zheng | [57] |
APPNL, APPNLF, and APPNLGF
| endogenous mouse App with humanized Aβ domain and (Swe (NL), Swe/Ibe (NLF), or Swe/Arc/Ibe (NLGF)) | Knock-in | Takaomi Saido | [58] |
PS1M146V
| endogenous mouse Psen1 (M146 V) | Knock-in | JAX 004193 | [214] |
PS1 KI | endogenous mouse Psen1 (P264L) | Knock-in | NA | [215] |
htau | complete human genomic MAPT (wt) with targeted disruption of murine Mapt
| PAC transgenic x Mapt KO | JAX 005491 | [37] |
Neurofibrillary tangles
Neurodegeneration
Cognitive impairment
Yin and yang of mouse models: Deciding between transgenics and knock-ins
Factors to bear in mind with knock-in models
Technical considerations for transgenic models
The transcript itself
The transgenic promoter
Strain background
Age of onset
Animal source
Sex as biological variable
Alternative approaches for transgene expression - viral gene delivery
Transgene | Promoter | Viral packaging | Host | Reference |
---|---|---|---|---|
Stereotaxically Targeted APP/Aβ Viral Transgenics
| ||||
BRI-Aβ40 BRI-Aβ42 | CBA | AAV1 | adult rat | [137] |
huAPP695 (Swe/Lon/Aus) |
(human?) EF1A
| AAV (serotype not stated) | adult mouse | [138] |
Stereotaxically Targeted Tau Viral Transgenics
| ||||
huMAPT
4R2N (P301L) | CAG | AAV2 | adult rat | [142] |
huMAPT
4R0N (P301S) | mouse Pgk
| lentivirus | adult mouse | [141] |
huMAPT
4R1N (P301L) | CMV | AAV2 | adult mouse | [216] |
huMAPT
4R2N (P301L) huMAPT
4R2N (wt) | human SYN1
| AAV1 | adult mouse | [217] |
huMAPT
4R1N (P301L) huMAPT
4R1N (wt) | CMV | lentivirus | adult rat | [140] |
huMAPT
4R2N (P301L) | human SYN1
| AAV9 | adult mouse | [218] |
huMAPT
4R0N (P301S) huMAPT
4R0N (wt) | mouse Pgk1
| AAV6 | adult mouse | [219] |
Whole-Brain Tau Viral Transgenics
| ||||
huMAPT (P301L) (isoform not stated) | CAG | AAV1 | neonatal mouse | [143] |
huMAPT
4R2N (P301L) | CAG | AAV1 | neonatal mouse | [220] |
Other tools for specific experimental needs - controllable transgenics
tTA-expressing driver lines
Model | Transgene | Promoter | Availability | Reference |
---|---|---|---|---|
tTA-Dependent Responder Lines
| ||||
tetO-APP Lines 102 and 107 | mo/huAPP695 (Swe/Ind) | TetO (first generation TRE from pTet-Splice) | MMRRC 34845-JAX, 34846-JAX | [69] |
rTg4510 | huMAPT4R0N (P301L) | TRE (first generation TRE from pTRE) | JAX 015815, 024854 | [29] |
rTg21221 | huMAPT4R0N (wt) | TRE (first generation TRE from pTRE) | Karen Ashe | [156] |
rTg9191 | huAPP695 (Swe/Lon) | TRE (first generation TRE from pTRE) | Karen Ashe | [155] |
hTau-A152T Line L1 | huMAPT4R1N (A152T) | TRE-Tight (second generation TRE) | JAX 028979 | [157] |
hTau-WT Line L32 | huMAPT4R1N (wt) | TRE-Tight (second generation TRE) | JAX 029269 | [157] |
tTA-Expressing Driver Lines
| ||||
Camk2a-tTA Line B | tTA (first generation) | moCamk2a
| JAX 007004, 003010 | [146] |
EC-tTA | tTA2 (second generation) |
Nop/Klk8
| MMRRC 031779-MU | [30] |
NEFH-tTA Line 8 | tTA (first generation) | human NEFH
| JAX 025397 | [147] |
ROSA:LNL:tTA | optimized/modified tTA (mtTA) | ROSA26-LNL (Cre-dependent)a
| JAX 011008 | [148] |
ROSA26-ZtTA | tTA (first generation) | ROSA26-CAG-LβL (Cre-dependent)b
| JAX 012266 (see also 024107) | [149] |
TRE-controlled responder lines
Transgene suppression with tet-off models
The value of tTA controls
Modeling LOAD - incorporating risk alleles for ApoE and TREM2
ApoE
Model | Allele | Targeting approach | Availability | Reference |
---|---|---|---|---|
ApoE Lines
| ||||
GFAP-ApoE3 Line 37, GFAP-ApoE4, Line 1 | huAPOE3 or E4 cDNA | Transgenic, huGFAP promoter | JAX 004633, 004631 | [196] |
ApoE2, E3, E4 KI | huAPOE2, E3, or E4
| Targeted insertion of APOE cDNAs | NA | [197] |
ApoE KO |
Apoe deletion (exon 3 replacement) | Targeted neo insertion replacing part of Apoe exon 3 | JAX 002052; 014556 | |
APOE*3, E*4 KI | huAPOE3 or E4
| Targeted replacement of Apoe exons 2–4 | JAX 027894 (E4) JAX 029018 (E3) | NA |
APOE2, E3, E4 Targeted replacement | huAPOE2, E3, or E4
| Targeted replacement of Apoe exons 2–4 | Taconic | |
TREM2 Lines
| ||||
TREM2 KO |
Trem2 deletion (exon 2–3 deletion) | Targeted lacZ/neo replacement of TREM2 exons 2–4 | UCD/KOMP VG10093 | [206] |
TREM2−/−
|
Trem2 deletion (exon 2–3 deletion) | Targeted deletion TREM2 exons 3–4 | Marco Colonna | [205] |
TREM2 KO |
Trem2 deletion (Q17X) | CRISPR/Cas9 targeted deletion | JAX 027197 | NA |
TREM2 R47H KI | endogenous mouse Trem2 (R47H) | CRISPR/Cas9 targeted mutation | JAX 027918 | NA |
TREM2 Y38C KI | endogenous mouse Trem2 (Y38C) | CRISPR/Cas9 targeted mutation | JAX 029725 | NA |
TREM2 p.T66 M | endogenous mouse Trem2 (T66 M) | CRISPR/Cas9 targeted mutation | Christian Haass | [208] |
TREM2 flox |
Trem2
tm1c(EUCOMM)Wtsi
loxP-flanked mouse Trem2 exons 2–3 | Targeted insertion | JAX 029853 | NA |
TREM2
Conclusions
Model | Main features | Pros | Cons | Examples of use in AD research |
---|---|---|---|---|
Tg2576 | mid-life amyloid pathology (10–14 mo) | well-characterized, maintains aging feature of AD | high lethality on C57 background, Tg male aggressive and needs to be single-housed | |
APP/PS1 | early-onset (~6 mo) amyloid pathology | well-characterized, co-integrated transgenes breed as a single allele | like other co-integrated models, cannot control for independent transgene effects | |
5XFAD | juvenile-onset amyloid pathology (~3 mo) | rapid onset phenotype, co-integrated transgenes breed as a single allele | non-physiological combination of FAD mutations, marked intracellular Aβ accumulation | |
3xTg-AD | early- to mid-life amyloid pathology plus hyperphosphorylated tau | captures both Aβ and phospho-tau features of AD | variable pathology between colonies and sexes, genetic drift has been observed | |
rTg4510 | early-onset neurofibrillary tangles (~5–6 mo), severe neurodegeneration | temporally controllable, rapid onset phenotype, develops true NFT pathology, well-characterized | breeding complicated by need for two independent transgenes, 13-fold overexpression of tau protein | |
PS19 | mid-life neurofibrillary tangles (6–9 mo), marked neurodegeneration | single-transgenic model, mid-life onset allows use in experiments expected to either delay or exacerbate pathology | transgene expression in spinal cord causes paralysis by mid-life | |
APPNLF
| mid-life amyloid pathology (~12 mo for homozygote, but note >24 mo for heterozygote allele) | endogenous APP level, native human Aβ sequence | limited cognitive impairment, requires homozygous allele for mid-life onset | |
APPNLGF
| juvenile-onset amyloid pathology (~3–4 mo for homozygote, ~9 mo for heterozygote) | endogenous APP level, can be used as heterozygote | non-native Aβ sequence, mild cognitive phenotype | |
hTau | mid-life hyperphosphorylated tau (~6 mo) | near-endogenous level expression of all 6 human wild-type tau isoforms | complicated breeding of transgene on null background, mild phenotype variable between colonies | |
APOE2, E3, E4 Targeted replacement | allele-specific effects on Aβ, tau, brain atrophy, and neuroinflammation; both central and peripheral functions influenced by allele | widely-studied, expressed at endogenous levels, mouse ApoE deleted | cannot distinguish central vs. peripheral effects; available through Taconic but with restrictions on usage |