Comments

1. • Ju-Hyun Lee
     Nathan Kline Institute/NYU Langone Med
   • Ralph Nixon
     New York University School of Medicine/Nathan Kline Institute
   • Posted: 02 Dec 2022

   This report by Yan and colleagues adds to the steadily emerging genetic and pathological evidence that the endosomal-lysosomal-autophagy (ELA) axis is likely a primary catalyst and driver of Alzheimer’s disease pathogenesis. Their work convincingly links the lysosomal protein, PLD3, an AD risk factor, to the disruption of this axis within neurons, leading to plaque-associated axonal spheroids and interruption of neuronal circuits. Notably, similar autophagy-related vesicles containing Aβ massively accumulate in the perikarya of selected neurons at a very early stage of disease in mouse AD models as a result of failing acidification of autolysosomes (Lee et al., 2022). This early pathobiology arising within neurons is the origin of the amyloid deposited extracellularly. Consistent with the conclusion in Yan et al., certain hallmark lesions in AD may develop due to earlier ELA dysfunction. It would be exciting for this investigative team to examine how the striking perikaryal autophagic stress visible at the earliest stages of disease in the 5xFAD model relates to the axonal dystrophy more prominent in the older animals.

   The fascinating new findings of Yan et al. confirm and extend our studies (Lee et al., 2011) demonstrating selective stalling of retrogradely moving autophagic/amphisomal vesicles, and their accumulation selectively within axonal swellings in primary cortical neurons treated with an inhibitor of lysosomal cathepsins or acidification. We also recently reported a similar phenomenon and mechanism in an FAD mutant PSEN1 knock-in mouse, which we showed develops a late-age onset axonal dystrophy, also characterized by selective accumulation of degradative vesicles within the axon swellings (Lie et al., 2022). Pearl Lie demonstrated selectively impaired retrograde transport of pH-deficient autophagic/amphisomal vesicles in primary cortical neurons from this mouse. These studies extend our earlier reports that PEN1-dependent lysosomal acidification deficiency arises from defective vATPase subunit maturation (Lee et al., 2010; Lee et al., 2015). This phenomenon could be reversed if proper lysosome acidity was restored by using one of several interventions. Since amyloid does not form in the PSEN1 KI mouse, the dynamic formation of dystrophic swellings is possible in this AD model in the absence of amyloid plaques (see also Lomoio et al., 2020). 

   References:

   Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun;25(6):688-701. Epub 2022 Jun 2 PubMed.

   Lee S, Sato Y, Nixon RA. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J Neurosci. 2011 May 25;31(21):7817-30. PubMed.

   Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A, Sato Y, Lie PP, Mohan P, Coffey EE, Kompella U, Mitchell CH, Lloyd-Evans E, Nixon RA. Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification. Cell Rep. 2015 Sep 1;12(9):1430-44. Epub 2015 Aug 20 PubMed.

   Lee S, Sato Y, Nixon RA. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy. J Neurosci. 2011 May 25;31(21):7817-30. PubMed.

   Lie PP, Yoo L, Goulbourne CN, Berg MJ, Stavrides P, Huo C, Lee JH, Nixon RA. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci Adv. 2022 Apr 29;8(17):eabj5716. PubMed.

   Lomoio S, Willen R, Kim W, Ho KZ, Robinson EK, Prokopenko D, Kennedy ME, Tanzi RE, Tesco G. Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer's disease trigger BACE1 accumulation in axonal swellings. Sci Transl Med. 2020 Nov 18;12(570) PubMed.

   View all comments by Ju-Hyun Lee View all comments by Ralph Nixon
2. • Wim Annaert
     KULeuven & VIB
   • Zoë Van Acker
     VIB-KU Leuven Center for Brain & Disease Research
   • Markus Damme
     University of Kiel
   • Posted: 02 Dec 2022

   The authors investigated plaque-associated axonal spheroids (PAASs) in relation to calcium signaling and PLD3 expression. They suggest that PLD3 is mechanistically linked to the accumulation of enlarged endolysosomal compartments: overexpression leads to an increase and to spheroid enlargement whereas knockdown reduced it, improving network function.

   Although the study of PAAS is highly relevant to better understand their relevance to AD disease pathogenesis, it has already been reported that PLD3 accumulates in dystrophic neurites; but this is as well true for other AD-relevant proteins, such as BACE1, APP, etc. Moreover, it is unclear, or not studied, how the observations relate to the function of PLD3. While the authors suggest that PLD3 may function in multivesicular body (MVB) maturation, this is not supported by mechanistic data. Moreover, the active (processed) PLD3 enzyme is confined to lysosomes, where it has been reported to exert nuclease activity and/or phospholipase activity, although the latter may be more unlikely given that the second PDE domain, which is required for phospholipase activity, is mutated in PLD3. How this activity contributes to PAAS and the accumulation of enlarged endo-lysosomes is not addressed.

   Moreover, while the authors used overexpression of GFP-tagged PLD3, PLD3 does not tolerate tags that well (Gonzalez et al., 2018). Hence, overexpressed GFP-PLD3 may be mislocalized and/or not be processed/sorted to its active form in lysosomes, as evident from the broader distribution of GFP-PLD3 in spheroids, i.e., not restricted to Lamp1-positive organelles. The ectopic, non-lysosomal localization (and processing?) of PLD3 raises the question of whether interpretations would be physiologically relevant. Further, the authors show that overexpression of PLD3 does not impact APP processing. Although only addressed by one brief communication in Nature (Fazzari et al., 2017), most studies support an inverse correlation between PLD3 levels and dysregulation of APP processing (Mukadam  et al., 2018; Cruchaga et al., 2014; Nackenoff et al., 2021; Blanco-Luquin et al., 2018; Satoh et al., 2014).

   Moreover, when depleting PLD3 in their models, a reduction in spheroid size and decrease in endolysosomal compartments was noticed. Although PAAS specifically were not studied, this outcome seems contradictory to previous studies showing that PLD3 KO and PLD3 SNPs cause lysosomal dysfunction and enlargement (Demirev et al., 2019; Fazzari et al., 2017). Can the authors exclude that the sgRNAs they used in their study do not have off-target effects that could confound these observations?

   References:

   Gonzalez AC, Stroobants S, Reisdorf P, Gavin AL, Nemazee D, Schwudke D, D'Hooge R, Saftig P, Damme M. PLD3 and spinocerebellar ataxia. Brain. 2018 Nov 1;141(11):e78. PubMed.

   Fazzari P, Horre K, Arranz AM, Frigerio CS, Saito T, Saido TC, De Strooper B. PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PubMed.

   Mukadam AS, Breusegem SY, Seaman MN. Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing. Cell Mol Life Sci. 2018 Jul;75(14):2613-2625. Epub 2018 Jan 24 PubMed.

   Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M, UK Brain Expression Consortium, Hardy J, Ryten M, Trabzuni D, Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, Lupton MK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, Munger RG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K, Alzheimer’s Research UK Consortium, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, Kölsch H, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Brown K, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton AB, Hardy J, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kauwe JS, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 2014 Jan 23;505(7484):550-4. Epub 2013 Dec 11 PubMed.

   Nackenoff AG, Hohman TJ, Neuner SM, Akers CS, Weitzel NC, Shostak A, Ferguson SM, Mobley B, Bennett DA, Schneider JA, Jefferson AL, Kaczorowski CC, Schrag MS. PLD3 is a neuronal lysosomal phospholipase D associated with β-amyloid plaques and cognitive function in Alzheimer's disease. PLoS Genet. 2021 Apr;17(4):e1009406. Epub 2021 Apr 8 PubMed.

   Blanco-Luquin I, Altuna M, Sánchez-Ruiz de Gordoa J, Urdánoz-Casado A, Roldán M, Cámara M, Zelaya V, Erro ME, Echavarri C, Mendioroz M. PLD3 epigenetic changes in the hippocampus of Alzheimer's disease. Clin Epigenetics. 2018 Sep 12;10(1):116. PubMed.

   Satoh J, Kino Y, Yamamoto Y, Kawana N, Ishida T, Saito Y, Arima K. PLD3 is accumulated on neuritic plaques in Alzheimer's disease brains. Alzheimers Res Ther. 2014;6(9):70. Epub 2014 Nov 2 PubMed.

   Demirev AV, Song HL, Cho MH, Cho K, Peak JJ, Yoo HJ, Kim DH, Yoon SY. V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function. Neurobiol Dis. 2019 Sep;129:182-194. Epub 2019 May 20 PubMed.

   View all comments by Wim Annaert View all comments by Zoë Van Acker View all comments by Markus Damme
3. • Suhail Rasool
     TrueBinding
   • Posted: 05 Dec 2022

   This is an interesting paper, showing by high resolution imaging techniques that around each amyloid plaque hundreds of axons develop dystrophic neurites. It also provides pathological evidence that the endosomal-lysosomal-autophagy axis may be a primary catalyst and leads to pathogenesis in AD. The lysosomal protein, PLD3, also considered as an AD risk factor leading to plaque-associated axonal spheroids and interruption of neuronal circuits, is involved.

   In 2014 we published a similar study showing nuclear M78 and NeuN immunoreactivities are localized in the center of neuritic plaques, surrounded by M78 and APP-CTF positive dystrophic neurites in the 3xTg-AD mice model. Dystrophic neurites that are immunopositive for both M78 and APP-CTF are found surrounding DAPI and M78 positive cores. The idea that the chromatin at the center of the neuritic plaque is derived from neuronal nuclei is supported by the observation that most of the cores of neuritic plaques are positive for the neuronal nuclear marker, NeuN (Pensalfini et al., 2014).

   References:

   Pensalfini A, Albay R 3rd, Rasool S, Wu JW, Hatami A, Arai H, Margol L, Milton S, Poon WW, Corrada MM, Kawas CH, Glabe CG. Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol Dis. 2014 Nov;71:53-61. Epub 2014 Aug 1 PubMed.

   View all comments by Suhail Rasool
4. • Jaime Grutzendler
     Yale University
   • Posted: 08 Dec 2022

   We appreciate the previous comments on our paper.

   We would like to clarify a few things, especially with regards to comments by Annaert, Van Acker, and Damme. We agree that there is a lot to learn about how PLD3 dysfunction or accumulation in spheroids might lead to lysosomal abnormalities and subsequently to spheroid enlargement.

   However, a point made in the comment was that in our viral-mediated expression experiments, PLD3-GFP fusion might disrupt normal PLD3 function, therefore clouding the interpretability of our results. This statement is inaccurate, as our studies never used a PLD3-GFP fusion protein but rather a gfp-p2a-pld3 construct, where GFP and PLD3 are expressed independently.

   The commentators also raised the possibility that, in our CRISPR/Cas9 ko experiments, the results might not be specific but rather an off-target effect of the sgRNA. This point is a general concern for any experiment using CRISPR; however, in our case in separate experiments, we used two independent sgRNAs, showing target engagement, and the manipulations led to reduced spheroid size, reduced aberrant lysosomes and improved electrical conduction, consistent with our other findings. Thus, we think it is extremely unlikely that the improvement in axonal phenotype we observed is due to some other gene than the desired target, which was PLD3.

   With regard to whether our results agree or not with previous studies, the only thing we can say for certain is that the few functional papers available on PLD3 are in very different contexts, models, age, and cell types, and cannot be directly compared to our in vivo Alzheimer’s conditions. This does point to the complexity of these mechanisms and the importance of further research to better understand the endolysosomal and autophagy pathways in axons and their role in neurodegenerative disease.

   We do think that our study provides a nice framework for understanding axonal pathology in AD in an in vivo model. Dystrophic neurites have been known to exist for more than 100 years, and people routinely use them as a pathological hallmark in their studies. Our study has, for the first time, used a single-axon imaging, molecular, optical electrophysiological and computational approach to study these structures comprehensively. We think we provide compelling evidence of the importance of endolysosomal abnormalities associated with amyloid plaques in the disruption of axonal conduction and downstream neural circuits.

   Our study also highlights the potential reversibility of plaque-associated axonal spheroids and beneficial effects on interconnected neural circuits. Therefore, we think that current strategies for amyloid plaque removal are an insufficient approach, and addressing axonal spheroids as a therapeutic target is critical. Hopefully our study stimulates further mechanistic investigations and innovation on the best therapeutic approach.

   View all comments by Jaime Grutzendler
5. • Grace Stutzmann
     Rosalind Franklin University/The Chicago Medical School
   • Posted: 13 Dec 2022

   Dr. Grutzendler's study is an important contribution to the field. Its strength is that the findings link, through defects in endo-lysosomal handling, two seemingly distinct features of AD pathology—abnormal protein aggregates and neural circuit dysfunction. I'm intrigued because this nicely aligns with a recent study in my lab, which demonstrated that the lysosomes in AD lack proteolysis capacity due to a more alkaline pH, and it is consistent with engorged lysosomes and lack of corresponding protein degradation of amyloid (Mustaly-Kalimi et al., 2022).

   It is a bit harder to say if the lysosomes solely serve as the current sink, and/or the pathogenic protein aggregates compromising membrane integrity in axons/neurites cause ionic leaks—both could look similar physiologically in terms of AP conduction defects. But in concert with Randy Nixon's comments, there is accumulating evidence pointing to endo-lysosomal pathways as central components of pathophysiology in AD, and this study adds a compelling piece to that puzzle.

   References:

   Mustaly-Kalimi S, Gallegos W, Marr RA, Gilman-Sachs A, Peterson DA, Sekler I, Stutzmann GE. Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2211999119. Epub 2022 Nov 28 PubMed.

   View all comments by Grace Stutzmann
6. • Hitoshi Okazawa
     Tokyo Medical and Dental University
   • Hikari Tanaka
     Tokyo Medical and Dental University
   • Kyota Fujita
     Tokyo Medical and Dental University
   • Posted: 03 Jan 2023

   PAAS, PANTHOS, and TRIAD: The Trinity of Early Stage AD pathology?

   This highly interesting work makes a great contribution for understanding unsolved enigmas in Alzheimer’s disease. It reveals that accumulation of LAMP1-positive vesicles in the autophagy-lysosomal degradation pathways (Extended Data Fig 5 of Yuan et al.) causes axonal spheroids, which has been observed in various neurodegenerative diseases including Alzheimer’s, and that underlying this phenotype is PLD3, a protein abundant in endoplasmic reticulum, endosome, and lysosome. Importantly, these findings have close relationships with recent results on the early stage pathologies of Alzheimer’s disease (Fujita et al., 2016; Tanaka et al., 2020; Lee et al., 2022), as suggested by some comments on this page.

   Before addressing the critical commonness shared with recent results, we would like to point out some small issues in Yuan et al. First, the authors used ThioflavinS for detection of Aβ, and showed various sizes of Aβ accumulation. For instance, in Figure 1b it is definite that enlarged axonal terminals arising from the contralateral hemisphere surround Aβ accumulation. However, the ThioflavinS stain is very small and could be a single-cell size. The authors also showed some larger Aβ accumulations (Extended Data Fig 1b). As 5xFAD mice show intracellular Aβ accumulations (Oakley et al., 2006), we wonder how different sizes of “Aβ plaques” correspond to intracellular Aβ accumulation in a single neuron or at a few neurons or to extracellular Aβ accumulation derived from multiple neurons (Tanaka et al., 2020). We feel it might be better not to call a single-cell level of Ab accumulation an Aβ plaque, while extracellular versus intracellular Aβ accumulation remains a matter of discussion.

   Second, we wonder whether the axonal swelling surrounding a spot of Aβ accumulation (“stable” in Figure 1c) and the axonal swelling at a certain distance from Aβ accumulation (“dynamic” in Figure 1c) could be considered as a similar process, because an AAV-GFP-positive axon does not seem positive for LAMP1 (Extended Data Figure 1b), though this image might represent an exception.

   More broadly, the similarity of Yuan et al.'s findings to some recent results is very impressive. Our group revealed that degenerative neurites full of autophagosome were surrounding TRIAD necrosis of a single neuron caused by intracellular Aβ accumulation in 5xFAD and APP-KI mouse models as well as in human AD postmortem brains (Fujita et al., 2016; Tanaka et al., 2020). We also showed the molecular mechanism that HMGB1 released from necrotic neurons induces neurite degeneration via phosphorylation of a submembrane molecule MARCKS and neuronal death via phosphorylation of Ku70 (Fujita et al., 2016; Tanaka et al., 2020; Jin et al., 2021; Tanaka et al., 2021).

   

   Interestingly, we observed phospho-MARCKS-positive neurites (see image at right) like axon swellings reported in Yuan et al. The group of Ralph Nixon also observed a similar autophagosome-lysosome change and called it PANTHOS (Lee et al., 2022). They proposed a model that the structures full of autophagosome-lysosome protruded from a centrally located dying neuron with Aβ accumulation. According to Yuan et al., most of these structures are degenerative neurites coming from other neurons, such as neurons in contralateral hemisphere (see Figure 1b). This observation of degenerative neurites from other neurons full of autophagosome-lysosome matches very well with the findings described in Greenfield’s Neuropathology Textbook (Graham and Lantos, 2002) and observed by our previous reports (Fujita et al., 2016; Tanaka et al., 2020; Jin et al., 2021; Tanaka et al., 2021). However, we also think that some of these processes represent protrusions from the dying neuron located inside degenerative neurites.

   In Yuan et al., the authors injected Aβ and observed a similar phenomenon. This does not mean that this phenomenon is derived from cell signaling triggered by extracellular Aβ. Instead it could be a phenomenon induced by intracellular Aβ, because we previously revealed that injected Aβ is taken up by neurons and subcellularly transported to the autophagosome-lysosome degradation system to finally induce neuronal necrosis (Chen et al., 2015). 

   The important takeaway here is that three groups have independently observed the similar phenomenon (see image below) of a single cell, or a few cells, of necrosis surrounded by degenerative and swelling axons/neurites full of structures of the autophagosome-lysosome system. This indicates that this is in fact occurring in early stages of AD pathology.

   

   TRIAD, PANTHOS, and PAAS could reflect three aspects of a single phenomenon, i.e., degenerative/dystrophic neurites (red) around and at a little distance from neuronal necrosis (purple) caused by intra-neuronal Ab accumulation (green). Such neurites are full of organelles of the autophagosome-lysosome system.

   One of the remaining issues would be which molecules mediate axon swelling in the proximal and distal regions from neuronal necrosis. Yuan et al. revealed that PLD3 plays an essential role for axon swelling within axons. On the other hand, our group revealed that HMGB1 released from necrotic neurons triggers TLR4-MARCKS and TLR4-Ku70 signals to induce neurite degeneration (Fujita et al., 2016) and neuronal death (Tanaka et al., 2021), respectively. Interestingly, PLD3 has an activity of endolysosomal ssDNA exonuclease (Gavin et al., 2018) and plays a role in ssDNA-sensing by TLR9 in endosome and lysosome (Gavin et al., 2021). 

   It is possible that damage-associated molecular patterns (DAMPs) released from necrotic neurons, such as HMGB1, DNAs and Aβ, trigger axon swelling and other phenotypes of neurite degeneration (see image above). Further studies in the future will likely unravel the relationship between DAMPs and associated neurite changes.

   References:

   Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci. 2006 Oct 4;26(40):10129-40. PubMed.

   Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, Waragai M, Ohtomo G, Iwata A, Tagawa K, Atsuta N, Katsuno M, Tomita N, Furukawa K, Saito Y, Saito T, Ichise A, Shibata S, Arai H, Saido T, Sudol M, Muramatsu SI, Okano H, Mufson EJ, Sobue G, Murayama S, Okazawa H. YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology. Nat Commun. 2020 Jan 24;11(1):507. PubMed.

   Fujita K, Motoki K, Tagawa K, Chen X, Hama H, Nakajima K, Homma H, Tamura T, Watanabe H, Katsuno M, Matsumi C, Kajikawa M, Saito T, Saido T, Sobue G, Miyawaki A, Okazawa H. HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease. Sci Rep. 2016 Aug 25;6:31895. PubMed.

   Jin M, Jin X, Homma H, Fujita K, Tanaka H, Murayama S, Akatsu H, Tagawa K, Okazawa H. Prediction and verification of the AD-FTLD common pathomechanism based on dynamic molecular network analysis. Commun Biol. 2021 Aug 12;4(1):961. PubMed.

   Tanaka H, Kondo K, Fujita K, Homma H, Tagawa K, Jin X, Jin M, Yoshioka Y, Takayama S, Masuda H, Tokuyama R, Nakazaki Y, Saito T, Saido T, Murayama S, Ikura T, Ito N, Yamamori Y, Tomii K, Bianchi ME, Okazawa H. HMGB1 signaling phosphorylates Ku70 and impairs DNA damage repair in Alzheimer's disease pathology. Commun Biol. 2021 Oct 11;4(1):1175. PubMed.

   Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun;25(6):688-701. Epub 2022 Jun 2 PubMed.

   Graham DI, Lantos PL. Greenfield’s Neuropathology (2 Vol. Set). 7th Ed. vol. 2, 210

   Chen X, Kondo K, Motoki K, Homma H, Okazawa H. Fasting activates macroautophagy in neurons of Alzheimer's disease mouse model but is insufficient to degrade amyloid-beta. Sci Rep. 2015 Jul 14;5:12115. PubMed.

   Gavin AL, Huang D, Huber C, Mårtensson A, Tardif V, Skog PD, Blane TR, Thinnes TC, Osborn K, Chong HS, Kargaran F, Kimm P, Zeitjian A, Sielski RL, Briggs M, Schulz SR, Zarpellon A, Cravatt B, Pang ES, Teijaro J, de la Torre JC, O'Keeffe M, Hochrein H, Damme M, Teyton L, Lawson BR, Nemazee D. PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing. Nat Immunol. 2018 Sep;19(9):942-953. Epub 2018 Aug 13 PubMed.

   Gavin AL, Huang D, Blane TR, Thinnes TC, Murakami Y, Fukui R, Miyake K, Nemazee D. Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors. Nat Commun. 2021 Oct 7;12(1):5874. PubMed.

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References

News Citations

1. Behold PANTHOS, a Toxic Wreath of Perinuclear Aβ That Kills Neurons 5 Jun 2022
2. Phospholipase D3 Variants Double Sporadic AD Risk 13 Dec 2013

Research Models Citations

1. 5xFAD (B6SJL)

Paper Citations

1. Demirev AV, Song HL, Cho MH, Cho K, Peak JJ, Yoo HJ, Kim DH, Yoon SY. V232M substitution restricts a distinct O-glycosylation of PLD3 and its neuroprotective function. Neurobiol Dis. 2019 Sep;129:182-194. Epub 2019 May 20 PubMed.

Further Reading

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