A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

Shang, Yutong; Sun, Xiaoyan; Chen, Xiaoqin; Wang, QuanQiu; Wang, Evan J.; Miller, Emiko; Xu, Rong; Pieper, Andrew A.; Qi, Xin

doi:10.1007/s00401-022-02499-0

Cited by 3 publications

(4 citation statements)

References 79 publications

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“…Furthermore, AICD can inhibit the transcription of coiled-coil-helix-coiled-coil-helix domain containing 6 (CHCHD6). CHCHD6 regulates mitochondrial contact site and cristae organization [ 65 ]. When AICD is specifically targeted to mitochondria it induces apoptosis in a hippocampal cell line, and this effect could be rescued with antioxidants and caspase inhibitors [ 66 ].…”

Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). Decades of research describe a relationship between mitochondrial function and Aβ production. Amyloid precursor protein (APP), of which Aβ is generated from, is found within mitochondria. Studies suggest Aβ can be generated in mitochondria and imported into mitochondria. APP and Aβ alter mitochondrial function, while mitochondrial function alters Aβ production from APP. The role these interactions contribute to AD pathology and progression are unknown. Here, we discuss prior research, the rigor of those studies, and the critical knowledge gaps of relationships between APP, Aβ, and mitochondria.

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Section: The Effects Of App and App Processing On Mitochondriamentioning

confidence: 99%

Interactions between amyloid, amyloid precursor protein, and mitochondria

Wilkins

2023

Biochemical Society Transactions

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“…Genes associated with the coding SNPs as measured by PDC80 and MPR80 have been previously attributed to cognitive functions including smoking initiation ( OR10A6 ) and detoxification of drugs ( GST1 ) [ 29 , 35 , 36 ]. The coding SNP rs2272487 in CHCHD6 that overlapped as measured by both MPR80 and PDC80 groups was identified as having a proportionally higher OR for glaucoma non-adherence.…”

Section: Discussionmentioning

confidence: 99%

“…Due to the CHCHD6 being a mitochondrial gene, there is potential that there may be significant impact of mitochondrial genes or metabolic pathways that are associated with medication non-adherence [ 35 ]. Previous studied have implicated the role of CHCHD6 in neurodegenerative diseases such as Alzheimer’s disease [ 36 ]. Though few studies have been conducted on the function of ZMAT4 , it has been implicated in myopia as well as thyroid cancer [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence

Barr

Feehan

Tak

et al. 2023

IJMS

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Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41–71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients’ glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System’s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer’s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62–5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10–6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11–0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47–58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.

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“…APP has been found in the PM, endocytic compartment, ER and GA. The specific distribution of APP in subcompartments such as mitochondria-associated ER, trans-GA or lipid rafts is closely related to the differential processing of APP [ 11 , 221 , 244 , 245 , 278 , 299 , 306 – 308 ]. For amyloidogenic cleavage, APP must colocalize with β- and γ-secretases in the i.c.…”

Section: Cholesterol-dependent Aβ Formationmentioning

confidence: 99%

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol

Rudajev,

Novotny

2023

Cell Biosci

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Amyloid β is considered a key player in the development and progression of Alzheimer’s disease (AD). Many studies investigating the effect of statins on lowering cholesterol suggest that there may be a link between cholesterol levels and AD pathology. Since cholesterol is one of the most abundant lipid molecules, especially in brain tissue, it affects most membrane-related processes, including the formation of the most dangerous form of amyloid β, Aβ42. The entire Aβ production system, which includes the amyloid precursor protein (APP), β-secretase, and the complex of γ-secretase, is highly dependent on membrane cholesterol content. Moreover, cholesterol can affect amyloidogenesis in many ways. Cholesterol influences the stability and activity of secretases, but also dictates their partitioning into specific cellular compartments and cholesterol-enriched lipid rafts, where the amyloidogenic machinery is predominantly localized. The most complicated relationships have been found in the interaction between cholesterol and APP, where cholesterol affects not only APP localization but also the precise character of APP dimerization and APP processing by γ-secretase, which is important for the production of Aβ of different lengths. In this review, we describe the intricate web of interdependence between cellular cholesterol levels, cholesterol membrane distribution, and cholesterol-dependent production of Aβ, the major player in AD.

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A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

Cited by 3 publications

References 79 publications

Interactions between amyloid, amyloid precursor protein, and mitochondria

Interactions between amyloid, amyloid precursor protein, and mitochondria

Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence

Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol

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