MAM and C99, key players in the pathogenesis of Alzheimer’s disease

Pera, Marta; Montesinos, Jorge; Larrea, Delfina; Agrawal, Rishi R.; Velasco, Kevin R; Stavrovskaya, Irina G.; Yun, Taekyung D; Area‐Gómez, Estela

doi:10.1016/bs.irn.2020.03.016

Cited by 20 publications

(17 citation statements)

References 231 publications

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“…Cholesterol disturbance at the MAMs of intracellular lipid rafts promotes amyloidogenic APP processing 23 . Accumulation of the APP proteolytic fragment C99 at the MAMs disrupts cholesterol trafficking and homeostasis 62 .…”

Section: Discussionmentioning

confidence: 99%

“…Hyperactivity of MAM tethering causes cholesterol accumulation and synaptic loss and is associated with cognitive deficits 21 . In addition, the cleaved product of APP (i.e., C99) accumulates at MAMs, where it impairs mitochondrial bioenergetics, disrupts cellular lipid homeostasis, and causes alterations in membrane lipid composition commonly observed during AD pathogenesis 22 , 23 . Despite these findings, the mechanism that links MAM impairment, cholesterol accumulation, and amyloidogenesis in AD remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

Zhao

Wang

et al. 2022

Nat Commun

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Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

Zhao

Wang

et al. 2022

Nat Commun

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“…The accumulation of phospholipids and cholesterol resulted from the dysfunction of ER‐Mt communication as second messengers triggers multiple signaling cascades, induces the transcription of drug efflux transporter genes and forms molecular phenomes of cell sensitivity to drugs through alterations of metabolic reprogramming. 34 Thus, the ER‐Mt communication can change cell sensitivity to external agents and increase cell resistance against drugs. 35 …”

Section: Er‐mt Communication With Lipid Transportsmentioning

confidence: 99%

New focuses on roles of communications between endoplasmic reticulum and mitochondria in identification of biomarkers and targets

Zhang

Yan

et al. 2021

Clinical & Translational Med

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The communication between endoplasmic reticulum (ER) and mitochondria (Mt) plays important roles in maintenance of intra‐ and extra‐cellular microenvironment, metabolisms, signaling activities and cell‐cell communication. The present review aims to overview the advanced understanding about roles of ER‐Mt structural contacts, molecular interactions and chemical exchanges, signal transmissions and inter‐organelle regulations in ER‐Mt communication. We address how the ER‐Mt communication contributes to the regulation of lipid, amino acid and glucose metabolisms by enzymes, transporters and regulators in the process of biosynthesis. We specially emphasize the importance of deep understanding about molecular mechanisms of ER‐Mt communication for identification and development of biology‐specific, disease‐specific and metabolism‐specific biomarkers and therapeutic targets for human diseases. The inhibitors and modulators of the ER‐Mt communication are categorized according to therapeutic targets. Rapid development of biotechnologies will provide new insights for spatiotemporally understanding the molecular mechanisms of ER‐Mt communication.

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“…Intact C99 may be directly involved in of some of the cellular pathologies associated with AD, such as defects in mitophagy, autophagy, mitochondrial structure, bioenergetics, lipid homeostasis, and AD-model animal behavior. (19)(20)(21)(22)(23)(24)(25) These discoveries suggest that C99 is itself directly involved in AD pathogenesis. Thus, a C99-specific binder that selectively inhibits its degradation would be a useful tool for further J o u r n a l P r e -p r o o f investigating the relationship between C99 and AD.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to their potential utility in reducing Aβ production, compounds that inhibit C99 cleavage would be valuable tool compounds for studying C99 biology. Intact C99 may be directly involved in some of the cellular pathologies associated with AD, such as defects in mitophagy, autophagy, mitochondrial structure, bioenergetics, lipid homeostasis, and AD-model animal behavior ( 19 , 20 , 21 , 22 , 23 , 24 , 25 ). These discoveries suggest that C99 is itself directly involved in AD pathogenesis.…”

mentioning

confidence: 99%

Verteporfin is a substrate-selective γ-secretase inhibitor that binds the amyloid precursor protein transmembrane domain

Castro

Parson

Beg

et al. 2022

Journal of Biological Chemistry

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MAM and C99, key players in the pathogenesis of Alzheimer’s disease

Cited by 20 publications

References 231 publications

ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

New focuses on roles of communications between endoplasmic reticulum and mitochondria in identification of biomarkers and targets

Verteporfin is a substrate-selective γ-secretase inhibitor that binds the amyloid precursor protein transmembrane domain

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