Transcriptional Effects of ApoE4: Relevance to Alzheimer’s Disease

ApoE4 competes for LDLR and LRP1 at glial cells and neuronal surface, preventing Aβ clearance and leading to its accumulation, enhancing oligomerization and senile plaque formation.

“ApoE4 competes for LDLR and LRP1 at the glial cells and neuronal surface, that are common to Aβ, preventing Aβ clearance and leading to its accumulation, that in turn enhance its oligomerization and the formation of senile plaques [43].”

LOAD patients carrying the ApoE4 allele, as opposed to ApoE3 carriers, show a decrease by about 50% in the levels of hippocampal IDE protein.

“LOAD patients carrying the ApoE4 allele, as opposed to ApoE3 carriers, show a decrease by about 50% in the levels of hippocampal IDE protein”

ApoE4 prevents Aβ enzymatic degradation through blockade of astrocytic NEP and MMP-9, or the extracellular insulin-degrading enzyme (IDE).

“ApoE4 also prevents Aβ enzymatic degradation, through the blockade of astrocytic NEP and MMP-9, or the extracellular insulin-degrading enzyme (IDE).”

ApoE4 is associated with decreased dendritic spine density and dendrite length, inhibition of neurite outgrowth and impaired neuronal plasticity, particularly in hippocampal pyramidal neurons.

“Another ApoE4-mediated effect at the synaptic level, are the decreased dendritic spine density and dendrite length, inhibition of neurite outgrowth and impaired neuronal plasticity [43], particularly in hippocampal pyramidal neurons [38].”

ApoE4 translocates to nucleus and has potential role as transcription factor.

“Another mechanism of action of ApoE4 that has been recently suggested is its translocation to the nucleus and potential role as a transcription factor [43].”

Sirt1 is involved in normal aging and has neuroprotective effects, such as promoting autophagy.

“Sirt1 is involved in normal aging and has neuroprotective effects, such as promoting autophagy [4,43]”

Alterations in gene expression associated with ApoE4 potentiate apoptotic and inflammatory pathways.

“the referred alterations in gene expression associated to ApoE4 potentiate apoptotic and inflammatory pathways [37,43]”

ApoE4, in mature or fragmented form, especially N-terminal, has high affinity for DNA, linking to promoter region of several genes.

“it has been shown that ApoE4, in its mature or fragmented form, especially the N-terminal, has a high affinity for DNA, linking to the promoter region of several genes.”

ApoE4 can act as transcriptional regulator of approximately 1700 genes, not only in neurons, but also in glial cells.

“Therefore, this protein can act as a transcriptional regulator of approximately 1700 genes [43], not only in neurons, but also in glial cells.”

ApoE4 directly interacts with promoter region of MADD, ADNP, COMMD6 and PPP2R5E genes, decreasing their expression.

“ApoE4 also directly interacts with the promoter region of MAPK activating death domain (MADD), activity dependent neuroprotector homeobox (ADNP), COMM domain containing 6 (COMMD6) and protein phosphatase 2, regulatory subunit B’, epsilon isoform (PPP2R5E) genes, decreasing their expression.”

ApoE4 signals for HDAC nuclear translocation, decreasing BDNF expression, crucial for synaptic plasticity.

“it signals for histone deacetylase (HDAC) nuclear translocation, decreasing BDNF expression, which is crucial for synaptic plasticity.”

By activating MAPK cascade, ApoE4 promotes APP expression and Aβ production.

“By activating a MAPK cascade, ApoE4 also promotes APP expression and Aβ production, proposing a clear impact on AD progression [43].”

PP2A expression is downregulated by direct transcriptional regulation of ApoE4, related to decrease in tau dephosphorylation, contributing to tau hyperphosphorylation.

“Another protein which expression is downregulated by the direct transcriptional regulation of ApoE4 is PP2A, which is related to a decrease in tau dephosphorylation [43], thus contributing to tau hyperphosphorylation, an important hallmark of AD.”