Table 3 Metabolic manipulations that enhance microglial Aβ phagocytosis in AD models

Microglia-specific HK2 depletion

5×FAD

Promotion of Aβ phagocytosis in vivo and in vitro

Increase in microglial LPL; activation of lipid metabolism

[16]

Supplementation with flavonoid—sodium rutin

APP/PS1 and 5×FAD

Enhancement of Aβ phagocytosis in vivo and in vitro

Microglial metabolic switch from anaerobic glycolysis to mitochondrial OXPHOS

[109]

Anti-TLR2 tretment

APP/PS1

Reduced Aβ plaque burden in vivo, enhancement of Aβ phagocytosis in primary mouse microglia

Restoration of oxidative metabolism and reduced inflammasome activation

[110, 111]

Treatment with the NAD⁺ precursor -nicotinamide riboside

APP/PS1

Increase in Aβ phagocytosis in vivo

Reduced neuroinflammation, activation of cyclic GMP-AMP synthase (cGAS)

[113]

Insulin administration

3×Tg-AD and APP/PS1

Reduced Aβ load in vivo studies; enhanced Aβ phagocytosis under inflammatory conditions in vitro (BV2 microglia)

Reduction in inflammatory markers

[114,115,116,117]

Supplementation with oleoylethanolamide and its analogue—KDS-5104

5×FAD

Reduced Aβ pathology in vivo; depletion of PPARα and CD36 antibody pretreatment reduced Aβ phagocytosis in vitro

Upregulation of PPARα-CD36 axis

[122]

S1P receptor 1 antagonist -ponesimod tretment

5×FAD

Amelioration of Aβ pathology in vivo; enhancement of Aβ phagocytosis in primary mouse microglia

Increase in the IL-33/Stat6 signaling pathway

[124]

Selective loss of Tsc1, a negative regulator of mTOR in microglia

5×FAD

Amelioration of Aβ pathology; enhancement of Aβ phagocytosis in vitro

mTOR activation and upregulation of TREM2; increase in expression of CD68 and LAMP1 in Tsc1-deficient microglia

[126]