Increased localization of <scp>APP</scp>‐C99 in mitochondria‐associated <scp>ER</scp> membranes causes mitochondrial dysfunction in Alzheimer disease

Pera, Marta; Larrea, Delfina; Guardia‐Laguarta, Cristina; Montesinos, Jorge; Velasco, Kevin R; Agrawal, Rishi R.; Xu, Yimeng; Chan, Robin B.; Paolo, Gilbert Di; Mehler, Mark F.; Perumal, Geoffrey S.; Macaluso, Frank; Freyberg, Zachary; Acı́n-Pérez, Rebeca; Enrı́quez, José Antonio; Schon, Eric A.; Area‐Gómez, Estela

doi:10.15252/embj.201796797

Cited by 175 publications

(233 citation statements)

References 76 publications

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“…Several reports have linked the intracellular accumulation of CTFβ to early neurodegenerative processes in AD (Xu et al, 2016;Lauritzen et al, 2016;Pera et al, 2017;Lauritzen et al, 2012). We found that the ΔDD and C259A alleles of p75 NTR significantly reduced the accumulation of this fragment in the hippocampus of 5xFAD mice, which, together with decreased Aβ plaque formation, could also contribute to their neuroprotective effects.…”

Section: Discussionmentioning

confidence: 99%

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Ibáñez

Goh

et al. 2020

Preprint

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A prevalent model of Alzheimer's disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. However, the molecular pathways that regulate APP internalization and intracellular trafficking in neurons are unknown.Here we report that 5xFAD mice, an animal model of AD, expressing signalingdeficient variants of the p75 neurotrophin receptor (p75 NTR ) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75 NTR knock-in mice lacking the death domain or transmembrane Cys 259 showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75 NTR interacts with APP and regulates its internalization in hippocampal neurons. Inactive p75 NTR variants internalized much slower and to lower levels than wild type p75 NTR , favoring nonamyloidogenic APP cleavage by reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75 NTR transmembrane domain may be an effective therapeutic strategy in AD. generation of all BACE-derived products, including Aβ, and constitutes the nonamyloidogenic pathway in APP processing. Cleavage by alpha-secretase generates a soluble N-terminal fragment (sAPPα) and a C-terminal stub (sCTFα) that can be further processed by gamma-secretase.Recent studies have indicated that, while cleavage by alpha secretases occurs at the plasma membrane, proteolytic processing by BACE requires APP internalization from the cell surface and thus mainly takes places in intracellular, endocytic compartments (Haass et al, 2012). Several studies have linked APP internalization to Aβ production (Koo & Squazzo, 1994; Selkoe et al, 1996), and complementary lines of evidence support this notion, including the requirement of low pH for BACE Ibáñez CF & Simi A (2012) p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity. Trends Neurosci 35: 431-440 Karran E, Mercken M & De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug (2012) The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus.

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Section: Discussionmentioning

confidence: 99%

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Ibáñez

Goh

et al. 2020

Preprint

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“…In cellular membranes, a pool of cholesterol in the PM is complexed with SM, preventing its mobilization (7,31), although treatment with SMases can release the membrane-bound cholesterol and induce its transport to the ER (30). Our previous data revealed that increases in MAM-localized C99 trigger the upregulation of SMase(s) activity (20). Thus, we asked whether the increases in cholesterol trafficking towards ER-MAM domains were a consequence of sustained SMase activity provoked by increases in MAM-C99.…”

Section: (Fig S1c)mentioning

confidence: 98%

“…MAM is a lipid raft in the ER (21,22), involved in the regulation of lipid homeostasis (23). We showed that in AD cell and animal models, there is an increased of C99 at MAM (20), resulting in the upregulation of MAM activities (22,24), including SMases, and cholesterol esterification by ACAT1 (20). Remarkably, inhibition of C99 production caused the inactivation of these MAM functions (20).…”

mentioning

confidence: 93%

The C99 Fragment Of App Regulates Cholesterol Trafficking

Pera

Larrea

Montesinos

et al. 2019

Preprint

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The link between cholesterol homeostasis and the cleavage of the amyloid precursor protein (APP), and their relationship to the pathogenesis of Alzheimer's disease (AD) is still unknown. Cellular cholesterol levels are regulated by a crosstalk between the plasma membrane (PM), where most of the cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol resides. This crosstalk between PM and ER is believed to be regulated by lipid-sensing peptide(s) that can modulate the internalization of extracellular cholesterol and/or its de novo synthesis in the ER. Our data here indicates that the 99-aa C-terminal fragment of APP (C99), a cholesterolbinding peptide, regulates cholesterol trafficking between the PM and the ER. In AD models, increases in C99 provoke the upregulation of cholesterol internalization and its delivery to the ER, which in turn result into the loss of lipid homeostasis and the appearance of AD signatures, such as higher production of longer forms of amyloid b. Our data suggest a novel role of C99 as mediator of cholesterol disturbances in AD, and as a potential early hallmark of the disease.The lipid composition of cellular membranes is adjusted constantly to regulate processes such as signal transduction and trans-membrane ionic gradients (1). To support these events, a network of enzymes interconnects the metabolism of all lipids, and controls the remodeling of the membrane into functional regions (2). Often, these functional regions have the characteristics of lipid-rafts or detergent-resistant domains (2). Lipid rafts are transient membrane subregions formed by local increases in cholesterol, which interacts with sphingomyelin (SM) and saturated phospholipids to shield cholesterol from the aqueous phase (2). These local elevations in cholesterol create highly ordered membrane microdomains that passively segregate lipid-binding proteins, thereby facilitating protein-protein interaction(s) and the regulation of specific signaling pathways (2). The formation of these domains is enabled by "lipid-sensing" proteins with the capacity to bind and cluster cholesterol (3). If the lipid-sensing proteins are eliminated from that domain, the lipid rafts are abrogated by hydrolysis of the "shielding" SM via activation of sphingomyelinases (SMases) that convert SM to ceramide (4). As opposed to SM, ceramide creates an unfavorable environment for cholesterol (5), which can then become accessible for removal via esterification (4). Hence, the turnover of lipid-raft domains and their capacity to regulate signaling pathways is tightly linked to the regulation of cholesterol homeostasis. Thus, alterations in the latter would affect the regulation of lipid raft formation, and vice versa.In the cell, cholesterol is either synthesized de novo in the endoplasmic reticulum (ER) or taken up as cholesterol esters (CEs) from lipoproteins (4). The de novo synthesis of cholesterol

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“…The enhanced MAM-mediated Ca 2+ transfer is observed in AD pathogenesis (190). MAM is a major intracellular site where presenilin locates and APP processing takes place (192,193), and the up-regulated Ca 2+ signal may result from the Ab-induced overexpression of Ca 2+ -transfer microdomain in the MAM (194); elevated ER-mitochondria apposition triggered by APP-processing by-product C99 (generated with soluble APPb in b-cleavage of APP) (195) or some FADrelated presenilin mutants (196,197); or the strengthened function of IP 3 R (as discussed in Influence of altered RyR, IP3R and STIM signal). Studies also suggested that only the mutations of PS2 (198), but not PS1, may lead to a closer coupling between the organelles, and the impact occurs in a mitofusin-2-dependent manner (199).…”

Section: Mam and Mptpmentioning

confidence: 99%

Ca²⁺homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

Wang

Zheng

2019

FASEB j.

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Emerging evidence indicates that Ca2+ is a vital factor in modulating the pathogenesis of Alzheimer's disease (AD). In healthy neurons, Ca2+ concentration is balanced to maintain a lower level in the cytosol than in the extracellular space or certain intracellular compartments such as endoplasmic reticulum (ER) and the lysosome, whereas this homeostasis is broken in AD. On the plasma membrane, the AD hallmarks amyloid‐β (Aβ) and tau interact with ligand‐gated or voltage‐gated Ca2+‐influx channels and inhibit the Ca2+‐efflux ATPase or exchangers, leading to an elevated intracellular Ca2+ level and disrupted Ca2+ signal. In the ER, the disabled presenilin “Ca2+ leak” function and the direct implications of Aβ and presenilin mutants contribute to Ca2+‐signal disorder. The enhanced ryanodine receptor (RyR)—mediated and inositol 1,4,5‐trisphosphate receptor (IP3R)—mediated Ca2+ release from the ER aggravates cytosolic Ca2+ disorder and triggers apoptosis; the down‐regulated ER Ca2+ sensor, stromal interaction molecule (STIM), alleviates store‐operated Ca2+ entry in plasma membrane, leading to spine loss. The increased transfer of Ca2+ from ER to mitochondria through mitochondria‐associated ER membrane (MAM) causes Ca2+ overload in the mitochondrial matrix and consequently opens the cellular damage‐related channel, mitochondrial permeability transition pore (mPTP). In this review, we discuss the effects of Aβ, tau and presenilin on neuronal Ca2+ signal, focusing on the receptors and regulators in plasma membrane and ER; we briefly introduce the involvement of MAM‐mediated Ca2+ transfer and mPTP opening in AD pathogenesis.—Wang, X., Zheng, W. Ca2+ homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles. FASEB J. 33, 6697–6712 (2019). http://www.fasebj.org

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Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Cited by 175 publications

References 76 publications

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

The C99 Fragment Of App Regulates Cholesterol Trafficking

Ca²⁺homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

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Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Cited by 175 publications

References 76 publications

Inactive variants of death receptor p75NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Inactive variants of death receptor p75NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

The C99 Fragment Of App Regulates Cholesterol Trafficking

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

Contact Info

Product

Resources

About

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Inactive variants of death receptor p75^NTRreduce Alzheimer’s neuropathology by interfering with APP internalization

Ca²⁺homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles