C99 selectively accumulates in vulnerable neurons in Alzheimer's disease

Pulina, Maria V.; Hopkins, Maya; Haroutunian, Vahram; Greengard, Paul; Bustos, Victor

doi:10.1016/j.jalz.2019.09.002

Cited by 60 publications

(40 citation statements)

References 33 publications

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“…We also unraveled the presence and activity of β-and γ-secretases in MAMs, thus allowing APP processing in this microdomain [20]. Importantly, we demonstrate herein that APP-CTFs accumulation also occurs in mitochondria of human AD brains in agreement with previous studies showing enhanced BACE1 and β-secretase-derived APP-CTF levels in autosomal-dominant AD human brain total extracts [25,62,66].…”

Section: Discussionsupporting

confidence: 89%

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

et al. 2020

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Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer’s disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD.

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Section: Discussionsupporting

confidence: 89%

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

et al. 2020

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“…This idea is supported by our data demonstrating that the C-terminal part of MT5-MMP interacts with C99, which may in addition assure the interactions of the canonical proteins previously described [12]. Deciphering the functional interactions between MT5-MMP and C99 is consistent with growing evidence implicating both proteins in the pathogenesis of AD [21,12,9,20,15,14].…”

Section: Functional Interactions Between the C-terminal Domain Of Mt5supporting

confidence: 87%

“…We next investigated how MT5-MMP could be functionally related to the immediate precursor of Aβ, C99, considering that it is drastically downregulated in 5xFAD mice deficient for MT5-MMP [12], and is increasingly considered to be a relevant neurotoxic factor in AD [8,11,15,14,33]. To test a possible functional interplay between C99 and one or several domains of MT5-MMP, we first mimicked AD-like C99 accumulation by transiently overexpressing a C99 construct in HEK cells.…”

Section: The C-terminal Domain Of Mt5-mmp Plays a Specific Role In Thmentioning

confidence: 99%

“…Thus, C99 accumulation occurs in the brains of the 3xTg and 5xFAD mouse models of AD, where it precedes that of Aβ [8,11,12,10]. C99 also accumulates in fibroblasts and brains of AD patients [13,14], as well as in human neurons derived from induced pluripotent stem cell (iPS) with AD familial mutations, resulting in pathogenic endosomal dysfunction and altered subcellular trafficking [15]. Taken together, these data are consistent with the contribution of C99 to the pathophysiology of AD and justify the study of APP metabolism beyond Aβ, including the role of proteinases involved in its regulation.…”

Section: Introductionmentioning

confidence: 97%

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MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

García-González

Paumier

Louis

et al. 2020

Preprint

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We previously discovered the implication of membrane-type 5-matrix metalloproteinase (MT5-MMP) in Alzheimer’s disease AD pathogenesis. Here we shed new light on pathogenic mechanisms by which MT5-MMP controls APP processing and the fate of amyloid beta peptide (Aβ), its precursor C99 and C83. We found in HEK carrying the APP Swedish familial mutation (HEKswe) that MT5-MMP-mediated processing of APP that releases the soluble 95 kDa form (sAPP95), was hampered by the removal of the C-terminal non-catalytic domains of MT5-MMP. Catalytically inactive MT5-MMP variants increased the levels of Aβ and promoted APP/C99 sorting in the endo-lysosomal system. We found interaction of C99 with the C-terminal portion of MT5-MMP, the deletion of which caused a strong degradation of C99 by the proteasome, preventing Aβ accumulation. These findings reveal novel mechanisms for MT5-MMP control of APP metabolism and C99 fate involving proteolytic and non-proteolytic actions mainly mediated by the C-terminal part of the proteinase.

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“…Moreover, processing of APP C‐terminal fragments (APP‐CTFs) occurs in detergent‐resistant membranes (DRMs) (Cordy et al , ). Notably, elevations in C99 have been shown to contribute to AD pathology (Shen & Kelleher, ), causing endosomal dysfunction (Jiang et al , ) and hippocampal degeneration (Lauritzen et al , ; Pulina et al , ).…”

Section: Introductionmentioning

confidence: 99%

The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

et al. 2020

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The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid-sensing peptide(s) in the ER that can cluster PM-derived cholesterol into transient detergent-resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol. When formed, these cholesterol-rich domains in the ER maintain cellular homeostasis by inducing cholesterol esterification as a mechanism of detoxification while attenuating its de novo synthesis. In this manuscript, we propose that the 99-aa C-terminal fragment of APP (C99), when delivered to the ER for cleavage by c-secretase, acts as a lipid-sensing peptide that forms regulatory DRMs in the ER, called mitochondria-associated ER membranes (MAM). Our data in cellular AD models indicates that increased levels of uncleaved C99 in the ER, an early phenotype of the disease, upregulates the formation of these transient DRMs by inducing the internalization of extracellular cholesterol and its trafficking from the PM to the ER. These results suggest a novel role for C99 as a mediator of cholesterol disturbances in AD, potentially explaining early hallmarks of the disease.

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C99 selectively accumulates in vulnerable neurons in Alzheimer's disease

Cited by 60 publications

References 33 publications

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

MT5-MMP controls APP and β-CTF/C99 metabolism through proteolytic-dependent and -independent mechanisms relevant for Alzheimer’s disease

The Alzheimer's disease‐associated C99 fragment of APP regulates cellular cholesterol trafficking

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