TABLE 2.
Interventions in APPswePS1dE9 mice indirectly affecting reactive astrocytes
| Intervention | Target | Age | Sex | Background | Amyloid‐beta | Astrocytes | Microglia | Synaptic density | Memory | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| Amyloid‐beta | ||||||||||
| Monthly immunization targeting Aβ42 from 3 mo | Aβ42 | 15‐16 mo | – | C57BL/6J × C3H/HeJ |
Cx and Hip: Aβ 42 area↓ (IHC) Aβ 42 ↓ (ELISA) |
Cx and Hip: GFAP↓ (IHC) | – | – | – | Qu et al. (2007) |
| Daily oral administration of Tannic acid from 6 mo | β‐secretase | 12 mo | F/M | C57BL/6J × C3H/HeJ† |
CC, ECx, and Hip: Aβ number and size↓ (IHC, 4G8) Wb: Aβ 40, Aβ 42 ↓ (ELISA) |
CC, ECx, and Hip: GFAP area↓ (IHC) | CC, ECx, and Hip: Iba1 area↓ (IHC) | – |
NOR↑ MWM↑ |
Mori et al. (2012) |
| c‐fms‐ACE 10/10 ‐APPswePS1dE9 c | Aβ42 | 5 mo1, 7 mo2, 8.5 mo3, 11–12 mo4 or 13 mo5 | F/M | C57BL/6 |
Cx and Hip: Aβ↓ 3 (IHC, 6E10 and ThS) Soluble Aβ 40 ↓ 2 Soluble Aβ 42 ↓ 1,2,5 (ELISA) |
GFAP area and number↓ 2,5 (IHC) | – | – | BM↑ 4 | Bernstein et al. (2014) |
| Weekly injection with low (L) or high (H) doses of IVIG 1, Oli‐Nabs 2 or Blue‐Nabs 3 | Aβ42 oligomers | 8–9 mo | M | C57BL/6J |
Aβ↓ 2H,3H (IHC, 6E10) Insoluble Aβ 40 ↓ 3H, ↔ 1,2,3L, Aβ 42 ↓ 3H, ↔ 1,2,3L Soluble Aβ 40 ↓, Aβ 42 ↓ H,2L, ↔ 1L,3L (ELISA) |
Cx: GFAP↓ 2,3H, ↔ 1,3L Hip: GFAP area↓ 2, ↔ 1,3 (IHC) |
Cx and Hip: Iba1↓ 2,3H, ↔ 1,3L (IHC) | Syn↑ 2H,3H, ↔ 1,2L,3L (WB) |
MWM↑ 2L,3H, ↔ 1,2H,3L NOR↑ |
Wang et al. (2016) |
| Bone marrow transplantation of WT1 or c‐fms‐ACE 10/10 2 mice at 2 mo | Aβ42 | 9 mo | F/M | C57BL/6J |
Cx: Aβ area↓ 2 (IHC, 6E10) Cx: Soluble Aβ 42 ↓ 2 (ELISA) |
Cx: GFAP area↓ 2, number↓ (IHC) | – | – | – | Koronyo‐Hamaoui et al. (2020) |
| Oral administration of BPN‐15606 from 3 mo1 or 6 mo2 | γ‐secretase | 6 mo1 or 9 mo2 | F | C57BL/6J × C3H/HeJ |
Cx: Aβ number and size↓ 1 (IHC, 82E1) Hip: Aβ size↓ 1 Cx and Hip: Aβ↔ 2 (IHC) Insoluble Aβ 38, Aβ 40 and Aβ 42 ↔ Soluble Aβ 38, Aβ 40 ↔ and Aβ 42 ↓ 1, ↔ 2 (ELISA) |
Cx and Hip: GFAP area and size↔ |
Cx and Hip: Iba1 area and number↓ 1, ↔ 2 (IHC) |
– | MWM↑ 1, ↔ 2 | Prikhodko et al. (2020) |
| Injection of IDOL ASO at 3 mo and 6 mo | Aβ | 8–9 mo | M | C57BL/6J |
Aβ area↓ (IHC, 82E1 and X‐34) (In)soluble Aβ 40, Aβ 42 ↓ (ELISA) |
GFAP area↓ (IHC) |
Iba1 intensity↔ Iba1 soma size↓ (IHC) |
– |
MWM↑ Contextual and cued FC↔ |
Gao et al. (2020) |
| Ad libitum access to Gemfibrozil 1 or Wy14643 2 via drinking water | Aβ | 8–10 mo | F/M | – |
Aβ↓ (IHC, 4G8) Cx and Hip: (in)soluble Aβ 40, Aβ 42 ↓ (ELISA) |
Cx and Hip: GFAP↑ (IHC and WB) | Cx and Hip: Iba1↑ (IHC and WB) | Cx and Hip: Syn and PSD95↑ (WB) |
MWM↑ Open Field test↑ |
Luo et al. (2020) |
| Gal‐3 +/− ‐APPswePS1dE9 c | Aβ | 7 mo | F/M | C57BL/6J × 129/Sv × SJL |
Hip: Aβ↓ (IHC) Aβ oligomers↓ (WB) |
Hip: GFAP↓ (IHC) | Hip: Iba1↓ (IHC) | – | MWM↑ | Tao et al. (2020) |
| Daily oral intake of Gallic Acid from 12 mo | α/β‐secretase | 18 mo | M | C57BL/6J | Cx, ECx, and Hip: Aβ area and number↓ (IHC, 4G8) | Cx, ECx, and Hip: GFAP area↓ (IHC) | Cx, ECx, and Hip: Iba1 area↓ (IHC) | – |
NOR↑ RAWM↑ YM↑ |
Mori et al. (2020) |
| Inflammation | ||||||||||
| Daily oral intake of PDTC from 9 mo | NF‐κB | 16 mo | – | C57BL/6J × C3H/HeJ † |
Cx: Aβ area↔ (IHC, pan‐Aβ, and ThS) Hip: (in)soluble Aβ 40, Aβ 42 ↔ (ELISA) |
Cx: GFAP intensity↔ (IHC) Cx: GLT‐1↑ (WB) |
Cx: CD11b↔ Cx: CD45 intensity↔ (IHC) |
– | MWM↑ | Malm et al. (2007) |
| LPS d/d ‐APPswePS1dE9 | Innate immune response | 13–15 mo | – | C57BL/6J × C3H/HeJ | – |
Cx: GFAP area↑ (IHC) GFAP↑ (WB) |
Cx: CD11b area↑ (IHC) CD11b↔ (WB) CD45↔ (IHC and WB) |
– | – | Jin, Kim, Maxwell, Li, and Fukuchi (2008) |
| Daily injection of PDTC | NF‐κB | 7–12 mo | – | C57BL/6J × C3H/HeJ | Cx and Hip: Aβ 40 ↔, Aβ 42 ↑ (ELISA) | Cx and Hip: GFAP↓ (IHC and WB) | – | – | – | Zhang et al. (2009) |
| Daily injection of Valproic acid from 7 mo | Inflammation/neuroprotection | 8 mo | – | C57BL/6J × C3H/HeJ |
Cx and Hip: Aβ area and number↓ (IHC, 4G8) Soluble Aβ 40, Aβ 42 ↓ (ELISA) |
Hip: GFAP number↓ (IHC) | Hip: Iba1 number↓ (IHC) | – | MWM↑ | Xuan et al. (2015) |
| Immunization with GA 1, Mo BM 2 or GA and Mo BM 3 from 10 mo | Myelin‐derived antigens/inflammation | 12 mo | M | C57BL/6J |
Cx and Hip: Aβ area↓ (IHC, 4G8, and ThS) Aβ 40, Aβ 42 ↓ (ELISA) |
Cx: GFAP area and number↓ (IHC) | – | Hip: VGluT1↑ (IHC) | BM↑ | Koronyo et al. (2015) |
| TRPA1 −/− ‐APPswePS1dE9 c | Inflammation/Calcium signaling | 8 mo | – | C57BL/6J | Aβ oligomers, monomers↓ (WB) | GFAP↑ (WB) | – | – |
MWM↑ YM↑ |
Lee et al. (2016) |
| NFATc2 −/− ‐APPswePS1dE9 c | Cytokines | 8 mo | M | C57BL/6J × 129X1/SvJ | Cx: Aβ intensity↔ (IHC, 4G8 and Campbell‐Switzer staining) | Cx: GFAP intensity↓ (IHC) | Cx: Iba1↔ and CD68 intensity↓ (IHC) | Hip: PSD95↓ and Syn↔ (WB) | – | Manocha et al. (2017) |
| Early postnatal antibiotic treatment for 1 wk from P14 | Inflammation | 6.5 mo | M | C57BL/6J × C3H/HeJ |
Aβ area↓ (IHC, 3D6) (In)soluble Aβ 40, Aβ 42 ↔ (ELISA) |
GFAP number↓ (IHC) | Iba1 number↓ (IHC) | – | – | Minter et al. (2017) |
| Daily administration of Humulus Japonicus from 5 mo | Oxidative stress/inflammation | 7.5 mo | F/M | C57BL/6J × C3H/HeJ | Cx: Aβ area↓ (IHC, BAM10) | Cx: GFAP area↓ (IHC) | Cx: Iba1 number↓ (IHC) | – |
NOR↑ YM↑ |
Park et al. (2017) |
| CCR3 −/− APPswePS1dE9 b | CCR3 | 12 mo | M | C57BL/6J × – | Cx and Hip: Aβ number↓ (IHC, 6E10) | Cx and Hip: GFAP number↓ (IHC) |
Cx and Hip: Iba1 number↓ (IHC) |
Hip: Drebrin and PSD95↑ (WB) Hip: Synapse number↑ (EM) |
MWM↑ | Zhu et al. (2017) |
| Weekly immunization with anti‐CD49d 1 or IgG control2 from 9 mo | Proinflammatory microglia | 10 mo | F | C57BL/6J |
Cx: (In)soluble Aβ 40, Aβ 42 ↔ (WB) Wb: Aβ↔ (IHC, 4G8) |
Cx: GFAP↓ 1, ↔ 2 (WB) Wb: GFAP↓ 1, ↔ 2 (IHC) |
Wb: CD68 and Iba1↓ (IHC) | Cx: Syn↔ and PSD95↓ (WB) | – | Manocha, Ghatak, Puig, and Combs (2018) |
|
ApoA‐I −/− ‐APPswePS1dE9 c KO was compared to hemizygous group |
ApoA‐I | 12 mo | F/M | C57BL/6J |
Cx: Aβ↑ (IHC) Hip: Aβ↔ (IHC) Hemisphere: (In)soluble Aβ 40, Aβ 42 ↔ (ELISA) |
Cx and Hip: GFAP area↑ (IHC) | – | – | Contextual and cued FC↔ | Button et al. (2019) |
| Daily oral administration of UA for 13 d from 7 mo | Inflammation | 7.5 mo | F | C57BL/6J × C3H/HeJ | Cx and Hip: Aβ 40, Aβ 42 number and area↓ (IHC) | Cx and Hip: GFAP number↓ (IHC) | Cx and Hip: Iba1 number↓ (IHC) | – | MWM↑ | Gong et al. (2019) |
| Two daily injections of YM344031 from 10 mo | CCR3 | 12 mo | M | C57BL/6J × C3H/HeJ | Hip and NCx: Aβ number↓ (IHC) | Cx: GFAP number↓ (IHC) | Cx: Iba1 number↓ (IHC) | Hip: Syn, drebrin and PSD95↑(WB) | MWM↑ | Sui et al. (2019 ) |
| pdMCAO 1 or sham‐operated 2 daily injection of ONO‐8713 for 14 d from 4.5 mo | EP1 receptor | 5 mo | M | C57BL/6J × C3H/HeJ | Cx: Aβ 40, Aβ 42 ↔ (ELISA) |
Cx: GFAP↔ Hip: GFAP↓ 2, ↔ 1 (IHC) |
Cx: Iba1↓ 1, ↔ 2 Hip: Iba1↔ (IHC) |
– | PAT↑ 1, ↔ 2 | Mendes et al. (2020) |
| Weekly injection of GA from 20 mo | Myelin‐derived antigens/Inflammation | 22 mo | F/M | C57BL/6J | Cx, ECx, and Hip: Aβ area↓ (IHC, 6E10) | Cx, ECx, and Hip: GFAP area↓ (IHC) | Cx, ECx, and Hip: Iba1 area↓ (IHC) |
ECx: PSD95↑ Hip and Wb: PSD95↔ (IHC) Syn↑ (MS) |
BM↑ | Doustar et al. (2020) |
| Transmitter release | ||||||||||
| Daily oral intake of selegiline for 3 d1, 1 wk2 or 3 wk3 from 10 mo | MAO‐B | 10–12 mo | F/M | C57BL/6J and C3H/HeJ | Aβ↔ 2 (WB) | GABA within GFAP positive area↓ 1 (IHC) | – | – |
MWM↔ 3 PAT↑ 2 |
Jo et al. (2014) |
| Boldine in drinking water from 6 mo | Hemichannel | 9 mo | F/M | C57BL/6J | Cx and Hip: Aβ area↔ (IHC) |
GFAP↔ (WB) d‐serine and GABA release↔ ATP and glutamate release↓ (CE‐LIF) |
Iba1↔ (WB) | Hip: RTN‐3 dystrophic neurites↓ (IHC) | – | Yi et al. (2017) |
| Daily oral intake of selegiline for 3 d1, 4 wk2 or KDS2010 from 8 mo3 | MAO‐B | 8 mo1, 9 mo2, or 13 mo3 | F/M | C57BL/6J × C3H/HeJ | – |
GABA within GFAP positive are↓ 1,3, ↔ 2 GFAP↓ 3 (IHC) |
– | – |
PAT↑ 1,3 , ↔ 2 MWM↑ 3 |
Park et al. (2019) |
| Neuroprotection | ||||||||||
|
Daily injection of Tetrahydrohyperforin (IDN5706) from 12 mo |
Inflammation, oxidative activity, and monoamines/neurotransmitter uptake | 13 mo | M | C57BL/6J × C3H/HeJ |
Hip: Aβ area↔ (IHC, Aβ1‐17) Aβ area↓ (IHC, ThS) |
Hip: GFAP number↔ Hip: GFAP intensity soma and soma size↓ (IHC) |
– | – | MWM↑ | Cerpa et al. (2010) |
| Daily administration of peroxisome proliferator WY 1 or 4‐PB 2 via drinking water from 7 mo | Peroxisomes | 9 mo | F/M | C57BL/6J × C3H/HeJ | Aβ area↓ (IHC, 4G8 and ThS) |
Cx: GFAP area↔ 1, ↓ 2 Hip: GFAP area↓ (IHC) |
Cx: CD11b area↔ 1, ↓ 2 Hip: CD11b area↓ (IHC) |
Hip: Syn, VAMP1/2 and VGlut1 ↔ GluR2, PSD95 and NR2B↑ (WB) |
MWM↑ NOR↔ |
Inestrosa et al. (2013) |
| Biweekly injection of recombinant NOIs vaccine from 2 to 3 mo | Neurite outgrowth | 5 mo | F/M | C57BL/6J | Cx and Hip: Aβ area and number↓ (IHC, 6E10) Hemisphere: Aβ↓ (WB, 6E10) | Cx and Hip: GFAP area↓ (IHC) | – | – | MWM↑ | Zhang et al. (2013) |
|
Endo‐B1 −/− APPswePS1dE9 c |
Apoptosis, autophagy, and mitochondrial function | 6 mo1 or 12 mo2 | M | C57BL/6J |
Cx and DG: Aβ area and number↑ 1 (IHC, 6E10) Soluble Aβ 40, Aβ 42 ↑ 1 (Luminex assay) |
Cx and Hip: GFAP area↑ 1 (IHC) |
– | CA3: Syn↓ (IHC) | MWM↓ | Wang et al. (2015) |
| Cofilin +/‐ ‐APPswePS1dE9 a | Filamentous actin | 7 mo | F/M | – × 129 5/SvEvBrd × C57BL/6J | – | Hip: GFAP intensity↓ (IHC) | – | Hip: PSD95 and Syn intensity↑ (IHC) |
Contextual FC↑ Cued FC↔ |
Woo et al. (2015) |
| Perinatal choline‐supplemented diet | Choline | 6 mo1, 9 mo2 or 12 mo3 | F/M | C57BL/6J × C3H/HeJ |
Hip: Aβ40, Aβ42 area↓2,3 Hip: Aβ 40, Aβ 42 number↓ 2,3 (IHC) Soluble Aβ↓ 2F,3M, ↔ 3F,2M (WB, 6E10) Soluble Aβ 40, Aβ 42 ↔ 1,2M,3F, ↓ 2F,3M (ELISA) |
GFAP↓ 2F , ↔ 3F,2M,3M (WB) | – | – | – | Mellott et al. (2017) |
| Daily injection of ASS234 from 10 wk | AChE/MAO | 4.5 mo | M | – |
Cx: Aβ↓ Hip: Aβ↔ (IHC, ThS) |
Cx: GFAP number↓ (IHC) | Cx: Iba1 number↓ (IHC) | – | – | Serrano et al. (2017) |
| Daily injection of liraglutide 1 or palm 11 ‐PrRP31 2 from 7 to 8 mo | GLP‐1 | 9–10 mo | M | C57BL/6J |
CX: Aβ area↔ Hip: Aβ area↔ 1, ↓ 2 (IHC) |
Cx: GFAP area↓ Hip: GFAP area↔ 1, ↓ 2 (IHC) |
Cx: Iba1 area↔ Hip: Iba1 area↔ 1, ↓ 2 (IHC) |
Hip: Syn↑ 2 (WB) | – | Holubová et al. (2019) |
| Pyk2 −/− ‐APPswePS1dE9 c | Pyk2 | 12 mo | F/M | C57BL/6J | Hip: Aβ area↔ (IHC) | Hip: GFAP area↓ (IHC) | Hip: Iba1 area↔ (IHC) | DG: PSD95 and SV2A area↑ (IHC) |
MWM↑ NOR↑ PAT↑ |
Salazar et al. (2019) |
| Oral administration of WBQ5187 from 6 mo | Multiple targets | 9 mo | M | C57BL/6J |
Aβ area↓ (IHC) Soluble Aβ 40, Aβ 42 ↓ (ELISA) |
GFAP↓ (IHC) | Iba1↓ (IHC) | – | MWM↑ | Wang et al. (2019) |
| Daily injections of liraglutide 1 or DA‐JC1 2 from 10 to 12 mo | GLP‐1 | 11–13 mo | F | C57BL/6J × C3H/HeJ | CA1, Cx, and DG: Aβ area↓ (IHC) | Hip: GFAP area↓ 2,↔ 1 (IHC) | Hip: Iba1 area↓ (IHC) | – | – | Salles et al. (2020) |
| Daily leptin injection for 1 wk from 3 mo1 or 12 mo2 | Neurogenesis | 3 mo or 12 mo | M | C57BL/6J | Hip: Aβ number↓ (IHC, 6E10) |
Hip: Gfap↔ 1, ↓ 2 (qPCR) SGZ: BrdU+GFAP+↔1, ↓2 SVZ: BrdU+GFAP+↔ (IHC) |
Hip: Iba1 number↓ (IHC) | – | – | Calió et al. (2021) |
| Environmental risk factors | ||||||||||
| Restraint stress for 21 d, 6 hrs a day from 4 mo | Stress | 5 mo | M | C57BL/6J | (In)soluble Aβ 40, Aβ 42 ↔ (ELISA) | Cx and Hip: GFAP area↑ (IHC) | – | – | – | Perez‐Nievas et al. (2011) |
| Five days a week: Low1 or high2 dose cigarette smoke exposure from 3 mo | Smoking | 7 mo | F/M | C57BL/6J × C3H/HeJ |
Cx: Aβ↔ 1, ↑ 2 Hip: Aβ area↑ Cx and Hip: Aβ number↔ 1, ↑ 2 (IHC, 4G8) Cx and Hip: Aβ area↔ 1, ↑ 2 Subiculum: Aβ area↔ (IHC, ThS) |
Cx and Hip: GFAP area↔ 1, ↑ 2 (IHC) | Cx and Hip: Iba1 area↔ 1, ↑ 2 (IHC) | – | – | Moreno‐Gonzalez et al. (2013) |
| Voluntary wheel running from 5 mo | Exercise | 7.5 mo | – | C57BL/6J × C3H/HeJ |
Cx: Aβ area↔ (IHC, 4G8, and ThS) Cx: Aβ number↓ (IHC, ThS) Hip: Aβ area↓ (IHC, A11, 4G8 and ThS) Hip: Aβ number↓ (IHC, ThS) |
Cx and Hip: GFAP intensity↓ (IHC) | – | – | MWM↑ | Tapia‐Rojas, Aranguiz, Varela‐Nallar, and Inestrosa (2016) |
|
Social housing: Social isolation1 Social contact with one2 or social contact with five3 from 6 mo |
Social interaction | 12 mo | M | C57BL/6J |
Hip: Aβ area and number↔ (IHC, ThS and 6E10) Aβ 40, Aβ 42 ↔ (ELISA) |
Hip: GFAP number↑ 3 (IHC) | – |
Syn, SNAP‐25, PSD95 and GluN2B↑ 3 GluA2 and GluN2A↔ (WB) Hip: Dendritic spine density↔ 1,2,↑ 3 (IHC) |
MWM↔1,2, ↑ 3 | Liang, Yang, Zhang, and Hao (2019) |
| Early life stress by limited nesting and bedding from P2‐9 | Early life stress | 4 mo1 or 10 mo2 | M | C57BL/6J | – |
ECx and Hip: GFAP area↔ (IHC) Hip: Aldh1l1, Aqp4, GFAP, GLAST, GLT1, GluS, Vim↔, Fasn↑ 1 (qPCR) |
– | – | – | Abbink et al. (2020) |
Abbreviations: General—Specified interventions or ages indicated with 1–5. When not indicated: the same effect for all interventions or ages. When a specific group is not indicated: read‐out was not determined for that group; ↑, increased or improved (Memory) compared to the control group of the same age; ↓, decreased or impaired (Memory); ↔, no (significant) difference; –, not studied; d, day(s); mo, month(s); wk, week(s). Intervention and target—Different APPswePS1dE9 strains indicated witha–c. aAPPswePS1dE9 mice, specific strain not indicated; bMMRRC Stock No: 34829‐JAX–C57BL/6J × C3H/HeJ; cMMRRC Stock No: 34832‐JAX—C57BL/6J. 4‐PB, 4‐phenylbutyrate: activates peroxisome proliferation; AChE, acetylcholinesterase; ApoA‐I, apolipoprotein A1: primary component of high‐density lipoproteins; ASS234, multipotent acetyl and butyrylcholinesterase/monoamine oxidase A–B inhibitor; Blue‐Nabs, naturally occurring autoantibodies against Aβ oligomers purified by Cibacron Blue; Boldine, inhibitor of hemichannel activity; BPN‐15606, γ‐secretase modulator; CCR3, C‐C chemokine receptor 3; CD49d, antibody against α4‐integrin; c‐fms‐ACE10/10, mouse line overexpressing angiotensin‐converting enzyme (ACE) under the control of the c‐fms promoter: resulting in ACE expression in myelomonocytic lineage cells; Cofilin, filamentous‐actin‐severing protein; DA‐JC1, Glucagon‐like peptide‐1 (GLP‐1)/glucagon‐dependent insulinotropic polypeptide dual agonist; Endo‐B1, endophilin‐B1 (Bif‐1: Bax‐interacting factor 1); GA, Glatiramer acetate: weak agonist of myelin‐derived antigens. Gal‐3, Galactin‐3: Aβ oligomerization and Aβ toxicity; Gemfibrozil, peroxisome proliferator‐activated receptor agonist; GLP‐1, glucagon‐like peptide‐1; IDOL ASO, inducible degrader of low‐density lipoprotein receptor (IDOL) antisense oligonucleotide (ASO); IVIG, intravenous immunoglobulin; KDS2020, reversible monoamine oxidase‐B inhibitor; Liraglutide, glucagon‐like peptide‐1 (GLP‐1) receptor analogue; LPSd/d, mouse line expressing a spontaneous mutation in the lipopolysaccharide (LPS) locus: resulting in a defective LPS response; MAO‐A‐B, monoamine oxidase‐A and B; MoBM, bone marrow‐derived CD115+ monocytes; NFATc2, nuclear factor of activated T cells, isoform c2; NOI, neurite outgrowth inhibitor; Oli‐Nabs, naturally occurring autoantibodies against Aβ oligomers purified by Aβ42 oligomers; ONO‐8713, Selective prostaglandin receptor 1 (EP1) antagonist; Palm‐PrRP, prolactin‐release peptide (PrRP) palmitoylated at the N‐terminus; pdMCAO, permanent middle cerebral artery occlusion; PDTC, pyrrolidine dithiocarbamate; NF‐κB, nuclear factor‐κB inhibitor; Pyk2, (PTK2B) Protein tyrosine kinase 2β; Selegiline, monoamine oxidase‐B inhibitor; Tannic acid, anti‐amyloidogenic polyphenol (flavonoid); TRPA1, transient receptor potential ankyrin 1: cation channel; UA, urolithin A; gut‐microbial metabolite of ellagic acid; WBQ5187, Quinolone‐benzofuran derivative; WT, wild‐type; WY, Wy‐14643 peroxisome proliferator‐activated receptor agonist: activators of peroxisome proliferators receptors agonist; YM344031, C–C chemokine receptor 3 antagonist. Age —at read‐out. Sex—female (F), male (M), or both (F/M). –, not indicated. Background: Genetic background of mice used in the study. x, Crossed with. †MMRRC Stock No: 34829‐JAX–C57BL/6J × C3H/HeJ crossed with C57BL/6J. Brain regions—CA, cornu ammonis; CC, cingulate cortex; Cx, cortex; DG, dentate gyrus; ECx, entorhinal cortex; Hip, Hippocampus; NCx, neocortex; SGZ, subgranular zone of the hippocampal dentate gyrus; SVZ, subventricular zone; Wb, Whole brain. Techniques—BM, Barnes Maze; BrdU, 5‐bromo‐2′‐deoxyuridine; CE‐LIF, capillary electrophoresis with laser‐induced fluorescence; ELISA, enzyme‐linked immunosorbent assay; EM, electron microscopy; FC, fear conditioning; IHC, immunohistochemistry; MS, mass spectrometry; MWM, Morris water maze; NOR, novel object recognition; PAT, passive avoidance test; RAWM, radial arm water maze; qPCR, quantitative polymerase chain reaction; WB, western blot; YM, Y‐Maze test. Genes, proteins, and transmitters—3D6, Aβ1–5 antibody. 4G8, Aβ17–24 antibody; 6E10, Aβ1–16 antibody; 82E1, Soluble and fibrillar Aβ; A11, oligomer antibody; Aβ, amyloid‐beta; Aldh1I1, 10‐formyltetrahydrofolate dehydrogenase; Aqp4, aquaporin‐4; ATP, adenosine triphosphate; BAM10, Aβ1‐40 antibody; CD, cluster of differentiation molecule; Fasn, fatty acid synthase; GABA, gamma‐aminobutyric acid; GFAP, glial fibrillary acidic protein; GLAST, glutamate–aspartate transporter; GLT‐1, glutamate transporter 1; GluA2, glutamate receptor, ionotropic, AMPA2 (alpha 2); GluN2A, glutamate receptor, ionotropic, NMDA2A (epsilon 1); GluN2B, glutamate receptor, ionotropic, NMDA2B (epsilon 2); GluR2, glutamate receptor 2; GluS, glutamate synthetase; Iba1, ionized calcium‐binding adapter molecule 1; NR2B, N‐methyl d‐aspartate receptor subtype 2B; PSD95, postsynaptic density protein 95; RTN‐3, reticulon‐3, marker of neuritic dystrophy; SNAP‐25, synaptosomal nerve‐associated protein 25; SV2A, synaptic vesicle glycoprotein 2A; Syn, synaptophysin; ThS, thioflavin‐S; VAMP1, vesicle‐associated membrane protein 1; VGlut, vesicular glutamate transporter; Vim, Vimentin; X‐34 dye, fluorescent amyloid‐specific dye.