Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease

Fragments of APOE, which are more abundant with APOE4 than with APOE3, can cause neuronal mitochondrial dysfunction in vitro.

“In vitro studies have shown that fragments of APOE, which are more abundant with APOE4 than with APOE3, can cause neuronal mitochondrial dysfunction165,166.”

Some studies indicated mitochondrial downregulation and decreased ATP production, contrary to the authors' findings of mitochondrial upregulation and enhanced ATP production in APOE4 cells.

“However, contrary to our findings of mitochondrial upregulation and enhanced ATP production in APOE4 cells, some studies indicated mitochondrial downregulation and decreased ATP production.”

Some ApoE4 mouse phenotypes are believed to arise from an allele-specific conformation of ApoE4.

“Some of these phenotypes are believed to arise from an allele-specific conformation of ApoE4: a unique arginine at position 112 (cysteine in the other two isoforms) shifts the hinge region of the protein, enabling the N-terminal domain (residues 1–167) to directly interact with the C-terminal domain (residues 206–299) [29].”

ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects.

“To answer this question, ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects.”

ApoE4 disrupts brain mitochondrial function via multiple mechanisms.

“given that ApoE4 disrupts brain mitochondrial function via multiple mechanisms (Chen et al., 2011; Nuriel et al., 2017; Tambini et al., 2016; Zhao et al., 2017b)”

ApoE fragments escape the secretory pathway into the cytosol.

“The resulting apoE fragments escape the secretory pathway into the cytosol”

The aberrant proteolytic processing of apoE4 and consequent neurotoxicity can be blocked by treating apoE4-expressing cells with small-molecule structure correctors, which convert apoE4 to an apoE3-like conformation and prevent apoE4 fragment generation.

“The aberrant proteolytic processing of apoE4 and consequent neurotoxicity can be blocked by treating apoE4-expressing cells with small-molecule “structure correctors,” which convert apoE4 to an apoE3-like conformation and prevent apoE4 fragment generation [12, 13, 18, 19].”

ApoE fragments engage in abnormal interactions in the cytosol that lead to neurodegeneration.

“where they engage in abnormal interactions that lead to neurodegeneration [17–19]”

Previous studies have linked each of the major Alzheimer's disease pathological alterations and brain aging to mitochondrial changes, which links ApoE4 to alterations in mitochondria and to Alzheimer's disease progression.

“previous studies have linked each of these pathological alterations and brain aging to mitochondrial changes, which in turn links ApoE4 to alterations in this organelle [22] and to AD progression.”

NSE-ApoE4 transgenic mice show deficits in learning and memory in an age-dependent way, more accentuated when ApoE4 is expressed by neurons rather than glial cells, compared to NSE-ApoE3 mice.

“NSE-ApoE4 transgenic mice showed deficits in learning and memory, in an age-dependent way, and these changes were more accentuated when ApoE4 was expressed by neurons rather than glial cells, when compared to NSE-ApoE3 mice [22].”

N2a cells stably expressing ApoE4 showed reduced levels of mitochondrial respiratory complexes (Cx) I, IV and V, while cortical neurons from NSE-ApoE4 showed reduced levels of all subunits, relatively to respective ApoE3-expressing controls.

“N2a cells stably expressing ApoE4 showed reduced levels of mitochondrial respiratory complexes (Cx) I, IV and V, while cortical neurons from NSE-ApoE4 showed reduced levels of all subunits, relatively to respective ApoE3-expressing controls.”

Recent in vitro studies found that apoE4 expressed in neurons, but not in astrocytes, reduces mitochondrial function.

“Recent in vitro studies have found that apoE4 expressed in neurons -but not in astrocytes - reduces the mitochondrial function [41].”

Chen and colleagues observed changes in respiratory chain complexes in neurons but not in astrocytes.

“Further, Chen and colleagues observed changes in respiratory chain complexes in neurons but not in astrocytes, indicating that mitochondrial dysfunction based on APOE4 expression is neuron-specific [32].”

APOE4 expression in N2A cells decreased the enzymatic activity of complex IV.

“APOE4 expression in N2A cells decreased the enzymatic activity of complex IV [32].”

Neuronal APOE4 expression reduced the levels of mitochondrial respiratory complex subunits compared to APOE3 neurons.

“Neuronal APOE4 expression reduced the levels of mitochondrial respiratory complex subunits compared to APOE3 neurons [32,33].”

Mitochondrial dysfunction based on APOE4 expression is neuron-specific.

“Further, Chen and colleagues observed changes in respiratory chain complexes in neurons but not in astrocytes, indicating that mitochondrial dysfunction based on APOE4 expression is neuron-specific [32].”

Several studies demonstrated a link between APOE4 and mitochondrial dysfunction, mainly in neurons.

“Several studies demonstrated a link between APOE4 and mitochondrial dysfunction, mainly in neurons9–11; yet the effect of APOE4 on mitochondrial dynamics was less studied.”

ApoE4-induced perturbation to fatty acid homeostasis underlies its negative effect on neuronal bioenergetic and synaptic function, in addition to its direct effect on mitochondria via domain interactions.

“Hence, our data suggest that ApoE4-induced perturbation to FA homeostasis underlies its negative effect on neuronal bioenergetic and synaptic function, besides its direct effect on mitochondria via domain interactions (Chen et al., 2011).”

In neurons, apoE4 is associated with neurotoxicity.

“and neurotoxicity [10, 17–19, 34, 35]”

ApoE4 reduces the level of respiratory chain subunits in Neuro-2a cells.

“ApoE4 also reduces the level of respiratory chain subunits in Neuro-2a (N2a) cells”

Expression of apoE4 in mouse neurons, but not astrocytes, selectively decreases the expression of mitochondrial respiratory subunits.

“Expression of apoE4 in mouse neurons, but not astrocytes, selectively decreases the expression of mitochondrial respiratory subunits [18].”

ApoE4 impairs respiratory function in Neuro-2a cells.

“and impairs respiratory function [18]”

In neurons, apoE4 is associated with impaired mitochondrial respiration.

“In neurons, apoE4 is associated with impaired mitochondrial respiration”

Previously, the authors showed that apoE4 decreases levels of cytochrome c oxidase 1 (COX1).

“Previously we showed that apoE4 decreases levels of cytochrome c oxidase 1 (COX1) [18], a mitochondrially encoded subunit that initiates complex IV assembly [82].”

Previously, the authors reported deficits in single subunits of each of the OXPHOS complexes in apoE4-expressing neuronal cells.

“Previously, we reported deficits in single subunits of each of the OXPHOS complexes in the apoE4-expressing neuronal cells [18].”

In APOE ε4 carriers, neuronal expression of ApoE4 has a neurotoxic effect, accelerating neurodegeneration and contributing to Alzheimer's disease progression.

“in the case of APOE ε4 carriers, neuronal expression of ApoE4 has a neurotoxic effect [22], accelerating neurodegeneration and contributing to AD progression.”

ApoE4 assumes a pathological conformation due to an interaction between arginine-61 and glutamate-255 at the N-terminal and C-terminal domains.

“ApoE4 assumes a pathological conformation due to the interaction between arginine −61 and glutamate −255, at the N-terminal and the C-terminal domains, respectively [22].”

These alterations in N2a cells matched decrease in mitochondrial total respiratory capacity, through lower OCR after CCCP in Seahorse experiments, relative to ApoE3 expression.

“These alterations in N2a cells matched the decrease in mitochondrial total respiratory capacity, through a lower OCR (oxygen consumption rate) after stimulation with CCCP (Carboxyl cyanide m-chlorophenyl hydrazone), a mitochondrial uncoupler, in Seahorse experiments, relatively to ApoE3 expression [22].”

Characteristic glucose hypometabolism was observed in cognitively normal ApoE4 carriers.

“a characteristic glucose hypometabolism was observed in cognitively normal ApoE4 carriers [22].”

Mutations in mtDNA are more common in brains of AD patients than in age-matched controls.

“Mutations in mitochondrial DNA (mtDNA) may be involved in mitochondrial dysfunction in AD, since they are more common in the brains of AD patients than in those of age-matched controls [22].”

ApoE4 is associated with deregulation in mRNA levels of genes encoding for subunits of mitochondrial respiratory complexes, encoded by nuclear and mitochondrial DNA.

“Other studies demonstrated that ApoE4 is associated to a deregulation in mRNA levels of genes encoding for subunits of mitochondrial respiratory complexes (Figure 1), encoded by nuclear and mitochondrial DNA [22]”

In ApoE4-expressing N2a cells, pharmacological treatment with GIND25 reverted some AD-related mitochondrial alterations, restoring Cx IV levels.

“In this respect, ApoE4-expressing N2a cells pharmacologically treated with GIND25, a small molecule that is able to disrupt ApoE4 domain interaction, reverted some AD-related mitochondrial alterations, namely by restoring Cx IV levels [22].”

In neurons, apoE4 is associated with decreased neurite outgrowth.

“decreased neurite outgrowth”

The APOE gene product appears to influence mitochondrial function.

“The APOE gene product, interestingly, also appears to influence mitochondrial function [164-167].”