Tian Q, Li J, Wu B, Pang Y, He W, Xiao Q, Wang J, Yi L, Tian N, Shi X, Xia L, Tian X, Chen M, Fan Y, Xu B, Tao Y, Song W, Du Y, Dong Z. APP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease. J Clin Invest. 2025 Jan 2;135(1) PubMed.
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NOVA Medical School
Congratulations to the authors. This study is fascinating, and the data convincingly demonstrate the critical role of the APP K612T mutation at the α-secretase site. It is well-established that BACE1 processing increases when APP escapes α-secretase cleavage. However, lactylation reduced both α- and β-secretase processing.
Some questions arose while reading.
Does the K612T mutation also interfere with BACE1 recognition, or only when K612 is lactylated? To strengthen their conclusions, it would be helpful to demonstrate in cells grown without lactate that the K612T mutation does not alter APP processing by BACE1.
Lactate levels probably fluctuate due to changes in cellular metabolism. Does the level of APP lactylation alongside? Additionally, it is crucial to investigate how lactate levels influence APP lactylation in neurons rather than in HEK cells. Given the distinct metabolic profiles of neurons compared to kidney-derived cancerous cells, this distinction is essential to validate the physiological relevance of the findings.
Despite these considerations, the study identifies a novel therapeutic strategy to decrease Ab production. The authors highlight how increasing APP endocytosis and lysosomal degradation in a CD2AP-dependent manner improves synaptic and memory impairments, which agrees with our previous findings (Ubelmann et al., 2016).
The experimental design is elegant, and the data are robust and convincing. However, the findings leave open questions: How do neurons respond to fluctuations in lactate levels? Moreover, does lactate decrease in the aging brain? Or is the decrease in the AD brain a consequence of the disease? This study opens new avenues of research that could lead to innovative therapeutic strategies targeting APP processing and Aβ reduction.
References:
Ubelmann F, Burrinha T, Salavessa L, Gomes R, Ferreira C, Moreno N, Guimas Almeida C. Bin1 and CD2AP polarise the endocytic generation of beta-amyloid. EMBO Rep. 2017 Jan;18(1):102-122. Epub 2016 Nov 28 PubMed.
View all comments by Claudia AlmeidaWeill Cornell Medicine/Burke Neurological Instiute
Cornell University
The paper by Tian et al. is an important addition to our understanding of the role of post-translational modifications in the regulation of metabolism and pathology. Numerous studies indicate that abnormal metabolism leads to altered function and pathology through post-translational modifications. As supported by this outstanding paper, this relationship appears critical in Alzheimer’s disease. Altered glucose metabolism has been known to accompany AD for decades, and the current paper helps fill the gap, linking it to plaques. Tangles are another major pathology in AD. If post-translational modifications are important in AD, they should interact with plaques and tangles. The role of post-translational modifications in AD has been especially well-documented for tau, including, but not limited to, phosphorylation, acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. How these modifications interact with tau to form tangles in the AD brain is not known. The current paper suggests a similar limitation occurs with our understanding of post-translational modification and plaque formation.
Lactate has been used as a reflection of altered metabolism for at least a century since the classic studies of Warburg in cancer cells (i.e., aerobic glycolysis). Aerobic glycolysis has been suggested to be critical in AD. The hundreds of papers that show altered lactate in multiple diseases or treatments have generally used lactate as an indicator of abnormal metabolism. Recent papers show lactate also alters metabolism and pathology by post-translationally modifying proteins.
Tian et al.’s work centers on APP lactylation at the critical K612 site. Decreased APP lactylation in AD suggests that K612 lactylation (K612la) of APP may diminish plaque formation. This is, apparently, in striking contrast to our studies on succinylation at the same site, which appears to promote plaque formation. Succinylation is regulated by the mitochondrial enzyme alpha-keto-glutarate dehydrogenase (KGDHC), while acetylation also occurs at the same site and is regulated by the mitochondrial enzyme pyruvate dehydrogenase. The reduced lactylation of APP-K612 in AD patients reported in this paper could be due to increased succinylation and/or other modifications at the same K612 site in AD brains, essentially competing for the same sites under relatively constant stoichiometry of APP. The difference in response to modifications of succinylation and lactylation on the same APP K612 site reflects potentially different mechanisms and thereby impacts its function in a complex manner. Interestingly, succinylation is linked to a mitochondrial enzyme, whereas lactylation occurs outside the mitochondria.
Multiple experiments in the paper consistently demonstrate that APP K612la and its mimic mutant K612T most likely affect APP trafficking, metabolism, and APP endosomal-lysosomal degradation rather than α-secretase cleavage and promotion of Aβ production. Additionally, the paper shows that APP lactylation is modulated by L-lactate treatment and that increased APP Kla levels reduce plaques and Aβ pathology. Curiously, reduced lactylation of APP-K was found in AD patients, whereas L-lactate increases APP lactylation and decreases plagues and Aβ pathology in AD.
Whether other post-translational modifications are interacting at this site remains to be determined. It should be noted that using K612T to mimic K612la may not be an ideal scenario, as chemically they are quite different: The lactylation of lysine contains a long seven-carbon side chain with hydroxyl group linked to C6 of the side chain, while threonine contains only a two-carbon side chain with hydroxyl group connected to C1. However, the observed difference between K612Q and K612T on the pathological progression of AD is quite surprising and remarkable. The data strongly suggest complex mechanisms underlying K612 modifications are related to AD pathology.
Developing drugs that ameliorate abnormal post-translational modifications is a challenge for the field. Thiamine deficiency has been associated with increased lactate and memory deficits since the 1930s. Considerable evidence suggests that the AD brain is thiamine deficient. In animal models, increasing thiamine decreases lactate, ameliorates KGDHC and PDHC abnormalities, diminishes plaques and tangles, and improves memory. Pharmacological thiamine showed encouraging changes in an AD pilot trial and is currently being tested in an NIH-supported multi-center trial.
The paper by Tian et al. is an important contribution toward developing new therapeutic avenues by targeting site-specific chemical modifications for treating AD.
View all comments by Sheng ZhangBoston University School of Medicine
The broader role of lactylation as a post-translational modification in Alzheimer’s disease and neurodegeneration was exemplified by this recent publication. The findings on the amyloid precursor protein (APP)/β-secretase (BACE1) endosome mechanism provide one explanation for the observation that treating an AD mouse model with L-lactate suppresses pathology. This is reminiscent to the finding three decades ago that the Swedish mutation favors BACE1 cleavage of APP in the secretory pathway (Haass et al., 1995). Lannfelt’s discovery of the Swedish mutation (Mullan et al., 1992) set the stage for the founding of BioArctic (2003) and the FDA approval of Lecanemab (2023). Will an AD therapy related to lactate pathway be a viable candidate for the FDA’s consideration in decades to come?
This study, along with earlier reports, illustrate that lactate can accumulate and influence protein modification, such as APP lactylation. While increased lactate levels were reported in cerebrospinal fluids of AD patients, CSF lactate does not directly reflect brain energy metabolism and thus is not a pathological biomarker for disease progression. On the contrary, a reduction of lactate may directly impact energy metabolism found in brains of AD patients and deprive neurons of an important fuel source. Therefore, efforts to provide brains with lactate either by feeding L-lactate as in this study, or restoring lactate production (e.g., by inhibiting indoleamine-2,3-dioxygenase 1 ) are valid approaches to deter AD onset or progression (Minhas et al., 2024).
Mechanistically, lactylation effects on epigenetic regulation may explain its impact on inflammatory pathways and functional outcomes related to neuronal synaptic plasticity. Tian et al. specifically focused on APP trafficking from the cell surface to endosomes where most enzymatic cleavages occur, i.e., the non-amyloidogenic α-secretase cleavage at cell surface versus amyloidogenic BACE1/g-secretase cleavages to generate Aβ protein in endosomes. The translational value of CD2AP as an interacting protein with lactylated APP is high. Tian et al. reported alteration of proteomic profiles related to trafficking in cellular endosomes-lysosomes as well as the metabolic processes of APP, which are the foundation for future target discovery and exploration for novel AD therapeutics.
References:
Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, Lannfelt L, Selkoe DJ. The Swedish mutation causes early-onset Alzheimer's disease by beta-secretase cleavage within the secretory pathway. Nat Med. 1995 Dec;1(12):1291-6. PubMed.
Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345-7. PubMed.
Minhas PS, Jones JR, Latif-Hernandez A, Sugiura Y, Durairaj AS, Uenaka T, Wang Q, Mhatre SD, Liu L, Conley T, Ennerfelt H, Jung YJ, Prasad P, Jenkins BC, Goodman R, Newmeyer T, Heard K, Kang A, Wilson EN, Ullian EM, Serrano GE, Beach TG, Rabinowitz JD, Wernig M, Suematsu M, Longo FM, McReynolds MR, Gage FH, Andreasson KI. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies. bioRxiv. 2024 Jun 28; PubMed.
View all comments by Weiming XiaNorthwestern University, Feinberg School of Medicine
In this article, Tian et al. provide a thorough interrogation of lactylation of the lysine at site 612 (K612) of APP695 and how this affects APP processing. Initial experiments in human AD brain show that lactylated APP is significantly lower in AD compared to control. Their further work entails interesting multidisciplinary approaches in both in vitro and in vivo models to dive deeper into the significance of this finding.
Through biochemical, pharmacological, and behavioral experiments, their work appears to show that lactylation facilitates the endocytosis of APP from the plasma membrane and into the early endosomes, possibly as a result of an inhibitory effect the lactylated form of APP may have on the α-secretase that it encounters. This is quite important because APP processing at the plasma membrane mainly occurs via cleavage by α-secretase, thus precluding the formation of toxic Aβ species (Lammich et al., 1999). If APP were instead to be shuffled to the early endosomes sans α-secretase cleavage, as this paper indicates happens at a higher rate when APP is lactylated, there would be concerns that APP would instead be cleaved by BACE1, whose activity is optimal in acidic compartments, such as the early endosomes (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999; Yan et al., 1999; Lin et al., 2000). Indeed, most sAPPβ is produced in these compartments and its counterpart, CTFβ, is then made readily available for cleavage by γ-secretase, which provides the opportunity for formation of toxic Aβ species.
However, the authors present an appealing finding: lactylated APP, although in close proximity to BACE1 in the same compartment, inhibits its binding as shown by co-IP assays, and is further supported by decreases in sAPPβ, CTFβ, and Aβs. Lactylated APP promotes CD2AP protein localization in the early endosomes, resulting in an increase in APP interacting with CD2AP, which in turn increases the degradation of APP through the endosomal-lysosomal network. Lastly, in mouse studies, the authors showed that lactyl-mimicking mutations had improved cognition.
In its entirety, this work is exciting and presents the idea that APP lactylation could be a novel target for research into new therapeutic strategies for AD. However, we must not forget that sAPPα, the fragment resulting from α-secretase cleavage of APP, is known to be neuroprotective in its own right (Furukawa et al., 1996; Goodman and Mattson, 1994; Smith-Swintosky et al., 1994). It will, therefore, become important to interrogate the mechanism by which lactylation facilitates APP endocytosis and whether there is indeed an inhibition of α-secretase cleavage, perhaps as a result of this lactylation occurring near the α-cleavage site. Additionally, probing the mechanism by which lactylation inhibits APP binding to BACE1 is the next logical step. Any future studies on potential therapeutic applications will need to keep in mind that there will likely be a need for a fine balance between sufficient cleavage of APP by α-secretase and minimal cleavage by BACE1.
References:
Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F. Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3922-7. PubMed.
Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, Smith TS, Simmons DL, Walsh FS, Dingwall C, Christie G. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol Cell Neurosci. 1999 Dec;14(6):419-27. PubMed.
Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999 Dec 2;402(6761):537-40. PubMed.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. PubMed.
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999 Dec 2;402(6761):533-7. PubMed.
Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PubMed.
Furukawa K, Sopher BL, Rydel RE, Begley JG, Pham DG, Martin GM, Fox M, Mattson MP. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem. 1996 Nov;67(5):1882-96. PubMed.
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View all comments by Justyna Dobrowolska ZakariaTel Aviv University
According to the amyloid cascade hypothesis, Aβ deposition is the main reason for neurofibrillary tangle formation and synaptic dysfunction, but evidence points toward pathological changes before Aβ and tau aggregates appear. Chronic neuroinflammation with sustained activation of microglia and astrocytes may lead to lesions in white-matter tracts and disrupt communication between neurons (Zhang et al., 2023). In AD, microglia activation and associated chronic release of inflammatory cytokines attenuate the cells’ capacity to clear toxic substances, which may also underlie myelin damage in this disease. Here, Tian et al. report that lactylation curbs Aβ production and plaque formation via lactate modification of specific lysines on amyloid precursor protein. This alters APP intracellular transport and degradation, limiting production and aggregation of Aβ; L-lactate injections slow amyloid accumulation and preserve memory in AD mice.
Recently identified, lactylation is a reversible, covalent, post-translational modification. It happens exclusively on lysine residues, where it influences protein structure, stability, localization, and protein-protein interactions. Conditions that elevate lactate, such as hypoxia, inflammation, or rapid glycolysis, can trigger this modification. Scientists have identified metabolic enzymes that indirectly facilitate lactylation, as well as delactylases that remove lactyl groups, but no dedicated lactyltransferases have been discovered as yet.
The authors injected L-lactate into the abdomens of APP23/PS45 mice for 90 days, beginning at 2 months old. By 6 months, the mice had more lactylated APP, fewer amyloid plaques, and did better in memory tests than untreated controls. These findings highlight lactylation as a potential novel regulatory mechanism in AD progression.
However, in animal models of neurodegenerative disease, reduced expression of monocarboxylate transporters (MCTs) was identified (Rabinovich-Nikitin et al., 2016; Zhang et al., 2018). In ALS, as in AD, it is a low content of cerebral lactate and lactate transporters which may lead to blockage of lactate transport from glia to neurons. L-lactate is an active metabolite capable of moving into or out of cells, acting as a signaling molecule, and regulating diverse physiological and pathophysiological pathways. Reduction of lactate may directly impact energy metabolism found in brains of AD patients and deprive neurons of an important fuel source. Therefore, efforts to provide brains with lactate by increasing the MCT1 transporters, either by feeding L-lactate as done in this study, or by restoring lactate production, e.g., by inhibiting indoleamine-2,3-dioxygenase, are valid approaches to protect the brain. Maintaining homeostatic circulating levels of lactate may mitigate neurodegenerative disease progression.
MCTs are a family of proton-linked plasma membrane transporters that allow the passage of monocarboxylates, including lactate, pyruvate, and ketone bodies. Of the 14 members of this family, only the first four have been recognized experimentally, each one with distinct substrate and inhibitor affinities. MCT1 is the most abundantly expressed lactate transporter in peripheral nerves. It has an essential role in axonal regeneration, is associated with oligodendrocytes, and recently has been implicated in the astrocyte-neuron lactate shuttle. On this basis, reduced expression of MCT1, MCT2 and MCT4 can impede lactate transport from glia to neurons, rendering neurons lactate deficient.
Related to this, we describe how CXCR4, a chemokine receptor protein with broad immune system regulatory functions, is involved in lactate transport to neurons. Expression of CXCR4 and functionally associated genes were altered in multiple neurodegenerative diseases. CXCR4 is of interest due to its involvement in chemotaxis, acting as a co-receptor for HIV-1 infection, and its critical role in development (Wang et al., 2022). Belonging to the family of G-protein-coupled receptors, CXCR4 selectively binds to the chemokine CXCL12. Receptor and ligand are expressed in various tissues, including the brain, and are directly involved in multiple biological processes.
The CXCR4/ CXCL12 (SDF1) axis is a major signal transduction cascade in inflammation and regulation of homing of hematopoietic stem cells (HSCs) within the bone marrow niche (Britton et al., 2021). This mechanism suggests that Aβ plaques attract microglia to activate the inflammatory cascade by which CXCL12 stimulates CXCR4-dependent signaling, both in microglia and astrocytes, to release pro-inflammatory cytokines such as TNFα. A Ca2+ cascade is likely involved based on this signaling mechanism, which ends in kinase activation, phosphorylation, and an excitotoxicity cascade triggered by excessive glutamate stimulation (Bezzi et al., 2001).
Therapeutically targeting the CXCR4/CXCL12 axis holds promise for treating a range of conditions, including neurodegenerative. While inhibiting this axis offers potential benefits, its physiological roles must be preserved to avoid adverse effects. Effort has been directed toward developing small-molecule and peptide-based CXCR4 antagonists for therapeutic use. Among these, only one small-molecule, reversible antagonist—AMD3100, aka Plerixafor—has received FDA approval (Hendrix et al., 2004).
AMD3100 has shown potential to attenuate neuroinflammation and facilitate the mobilization of HSCs from bone marrow into brain. Our findings, alongside those of others, demonstrate that AMD3100 treatment alleviates pathologies and cognitive deficits in AD mouse models (Kawanishi et al., 2018; Gavriel et al., 2020). Increased presence of HSC markers in the brains of treated mice suggests that these cells originate from bone marrow. Systemic administration of CXCR4/CXCL12 inhibitors such as AMD3100 may offer therapeutic benefits and address challenges associated with stem cell transplantation.
Pharmacologically induced mobilization of endogenous BMDCs through systemic administration of inhibitors targeting the CXCR4/CXCL12 axis has demonstrated benefits in alleviating pathologies associated with AD and ALS. We recently reported that inhibition with AMD3100 increased levels of the brain's major L-lactate transporter MCT1. ALS features deficiency in cerebral lactate and its transporters, and increasing MCT1 levels can facilitate lactate transport into and out of cells, potentially protecting neurons (Rabinovich-Nikitin and Solomon, 2022).
The tumor suppressor gene p53 has been implicated in regulating MCT1 expression. Under hypoxic conditions, loss of p53 promotes MCT1 expression, reducing the involvement of CXCR4 in cell death. This suggests a direct link between p53 and MCT1 expression, further highlighting the intricate interplay between various signaling pathways in neuroprotection and neurodegeneration (Boidot et al., 2012). In animal models, disruption of the lactate transporter MCT1 results in widespread axonal damage and neuronal death.
Upregulation of MCT1 by inhibition of the CXCR4/CXCL12 signaling axis led us to test the feasibility of combined AMD3100 and L-lactate treatment to attenuate neuroinflammation and stimulate remyelination in an Aβ-induced AD mouse model (Gavriel et al., 2022). The combination improved the cognitive deficit, reduced tau and APP pathologies and, most importantly, shifted microglia toward an anti-inflammatory M2 profile.
The CXCL12/CXCR4 axis represents a versatile target for therapeutic intervention, with reversible inhibitors like AMD3100 offering a unique mechanism to harness the regenerative potential of HSCs (Gavriel et al., 2025). By balancing mobilization, differentiation, and quiescence, AMD3100 and its derivatives provide a promising platform for addressing neurodegenerative diseases, chronic inflammation, and beyond. However, preserving physiological functions of the pathway is critical to maximizing benefits while minimizing side effects.
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Hendrix CW, Collier AC, Lederman MM, Schols D, Pollard RB, Brown S, Jackson JB, Coombs RW, Glesby MJ, Flexner CW, Bridger GJ, Badel K, MacFarland RT, Henson GW, Calandra G, AMD3100 HIV Study Group. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr. 2004 Oct 1;37(2):1253-62. PubMed.
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Gavriel Y, Rabinovich-Nikitin I, Ezra A, Barbiro B, Solomon B. Subcutaneous Administration of AMD3100 into Mice Models of Alzheimer's Disease Ameliorated Cognitive Impairment, Reduced Neuroinflammation, and Improved Pathophysiological Markers. J Alzheimers Dis. 2020;78(2):653-671. PubMed.
Rabinovich-Nikitin I, Solomon B. Lactate Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1G93A Mice' Life-Span. 2022 Jan 29 10.1101/2022.01.28.478264 (version 1) bioRxiv.
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Gavriel Y, Voronov-Goldman M, Solomon B. Reversible inhibition of chemokine receptor CXC4 signaling via AMD3100 mitigates neuroinflammation in Alzheimer's disease. http://dx.doi.org/10.20517/and.2024.25
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