Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons

Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons

This paper was about finding a small molecule aka drug to make ApoE4 more flexible. I just read the introduction, not the drug part.

——112 — 158
ApoE2 Cys Cys
ApoE3 Cys Arg
ApoE4 Arg Arg

The Cys-112 residue in apoE2 and apoE3 weakens the domain interaction, resulting in more open structures

ApoE4 displays an intramolecular domain interaction between its amino- and carboxyl-terminal domains, leading to a compact structure (12, 13).

In plasma, apoE4 binds preferentially to very low density lipoproteins (12, 13).

The Cys-112 residue in apoE2 and apoE3 weakens the domain interaction, resulting in more open structures (13).

In neurons, apoE4 reduces expression of the protein subunits of mitochondrial respiratory complexes, such as subunit 1 of complex IV (mtCOX1) and subunit α of complex V, resulting in a reduction in mitochondrial respiratory function

apoE4 perturbs neuronal function by reducing mitochondrial motility, decreasing neurite outgrowth (17–19), and inhibiting synaptogenesis (20)

The neuropathological features of apoE4 include

All the shi* that goes on because of ApoE4

  • impaired neurite outgrowth (17–19)
  • disruption of the cytoskeleton in neurons (38), including increased Tau hyperphosphorylation (39, 40);
  • mitochondrial dysfunction in neurons, including altered mitochondrial membrane potential (36) and decreased respiratory enzyme levels and activity (16);
  • impaired neuronal mitochondrial motility (current study);
  • impaired synaptogenesis (20, 24);
  • enhanced susceptibility to neuron-specific proteolysis and neurotoxic fragment formation (39–41)
  • increased amyloid β production (21);
  • increased neuronal lysosomal leakage and apoptosis (42);
  • CNS neuropathology and impaired behavioral activity (26, 27, 41, 43)
  • enhanced amyloid β deposition (44–47).

Read references 12 & 13 because they describe protein structure.