Kumar M, Wu Y, Knapp J, Pontius CL, Park D, Witte RE, McAllister R, Gupta K, Rajagopalan KN, De Camilli P, Ryan TA. Triglycerides are an important fuel reserve for synapse function in the brain. Nat Metab. 2025 Jul 1; Epub 2025 Jul 1 PubMed.
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University of Kansas
This is a very interesting study that challenges some existing conceptions and brings to the fore questions about brain energy metabolism. It counters a pre-existing notion that neurons are not enthusiastic about catabolizing fatty acids through mitochondrial -oxidation to generate energy, presumably because neurons require a lot of membrane production and it may behoove neurons not to catabolize fatty acids. This paper turns that idea on its head, or at least indicates that broad assumptions may go too far.
Here, it certainly seems that some neuron populations, in some instances (for example at active synapses) can, and perhaps eagerly do, pursue β-oxidation. One might argue that these experiments are in some ways susceptible to the usual limitations that accompany the use of model systems, and some data streams used to argue the conclusions could have benefitted from added rigor. One example would be confirming that the neutral lipid deposits referred to as lipid droplets are in fact lipid droplets, as opposed to lysosomal lipid.
Technical caveats aside, and although this was not specifically designed as an “AD study,” it has AD ramifications. It provides some insight into lipid accumulations in AD brains. It emphasizes a point that I think is quite central to AD, which is that it is virtually impossible to disentangle lipid and mitochondrial metabolism from each other. It raises a very interesting point about a cycle called the “Randle Cycle,” which I had not previously considered. The Randle cycle refers to a reciprocal relationship between glucose and lipid-fueled bioenergetic activity. It is interesting to consider what such a balance looks like in the AD brain.
Finally, this paper pulls into the discussion ApoE, and presents what I think is a reasonable angle from which to consider ApoE’s mechanistic connection to AD.
Overall, this is a very interesting read.
View all comments by Russell SwerdlowNational Institutes of Health
This study provides compelling evidence that neurons can use triglyceride-rich lipid droplets to support synaptic activity. This work challenges the long-held view that neurons rely exclusively on glucose, and it reveals a previously underappreciated flexibility in neuronal bioenergetics.
Using a combination of elegant neuronal stimulation and inhibitor experiments, the authors show that activity-induced breakdown of synaptic lipid droplets via the lipase DDHD2 fuels mitochondrial β-oxidation. Extending these findings in vivo, this study demonstrates that neuronal β-oxidation is essential to prevent a torpor-like state in mice.
These findings shift our understanding of how neurons meet their energetic demands and open important mechanistic and physiological questions. What molecular pathways link neuronal activity to lipid droplet lipolysis and fatty acid import into mitochondria? Does neuronal reliance on β-oxidation become more pronounced in conditions of limited glucose, such as during aging or in disease states? And do alterations in lipid droplet dynamics—either within neurons or in neighboring glia, potentially involving intercellular lipid transfer—modulate this metabolic flexibility?
With lipid droplets gaining increasing attention in the context of multiple neurodegenerative diseases, these findings invite broader consideration of how fatty acid metabolism may shape neuronal function and vulnerability, beyond the context of hereditary spastic paraplegias.
View all comments by Priyanka NarayanBrigham & Women's Hospital/Harvard Medical School
Healthy neurons provide a stubborn environment for lipid droplets (LDs) to thrive, due to the cellular machinery that enables rapid synthesis and degradation of triglycerides, a principal component of LDs. Decreasing the activity of the neuronal lipase DDHD2, which is responsible for the accelerated catabolism of triglycerides, results in the accumulation of LDs in otherwise healthy neurons. We have adapted this approach to investigate whether triglyceride-rich LDs influence the physiological states of α-synuclein (Bolsinger et al., 2025), an abundant brain protein involved in regulating neurotransmission.
Though neurons heavily depend on glucose for energy, under hypoglycemic states they utilize ketones, a precursor for lipid synthesis in the brain, to meet their energy demands. Here, the Ryan lab combined KLH45, a small-molecule inhibitor of DDHD2, with multiple approaches to elegantly demonstrate that neuronal lipids, particularly triglyceride-rich LDs, can efficiently serve as a fuel source for synaptic vesicle recycling during hypoglycemia.
Some open questions that remain include:
References:
Bolsinger MM, Moors TE, Brontesi L, Nuber S, Dettmer U, Ramalingam N. Acute lipid droplet accumulation induced by the inhibition of the phospholipase DDHD2 does not affect the level, solubility, or phosphoserine-129 status of α-synuclein. Metab Brain Dis. 2025 Jan 24;40(1):111. PubMed.
View all comments by Nagendran RamalingamHenan Academy of Innovations in Medical Science
These findings are very interesting in the context of Alzheimer’s disease. We know that glucose utilization is impaired in AD brains. 18FDG-PET scans have demonstrated impaired glucose uptake in individuals with mild cognitive impairment (MCI), early AD, and a family history of developing AD (Edison et al., 2008; Mosconi et al., 2010; Bailly et al., 2015). In fact, these hypometabolic changes precede the appearance of dementia symptoms by a decade or more (Raut et al., 2023; Yonamine et al., 2023; de la Monte, 2024).
In order to compensate for loss of glucose utilization, lipids are broken down to ketones by astrocytes and "shipped" to neurons to be directly turned into ATP by mitochondria without the need for glycolysis. If the supply of ketones is inadequate, glia cells can break down the myelin sheath of axons in white-matter sections of the brain, which is made of lipids, to produce ketones. This is the reason why white-matter loss is found in AD brains (Makino et al., 2014; Yassine et al., 2022). The lipid stores in glia can be seen under the microscope as lipid droplets. In fact, the earliest evidence of disturbed energy utilization in the brain came from Alois Alzheimer’s description of the first AD brain tissue analysis, where he noticed that cells contained lipid droplets that are not normally seen in the brain (Alzheimer et al., 1995; Foley, 2010).
APOE is a lipid transporter in the brain and we know that the allele ApoE ε4 is a risk factor for AD (Corder et al., 1993). Studies showed that the levels of cholesterol and LDL lipid transporters is changed in carriers of the ApoE ε4 allele and even more so in those who have developed AD (Xu et al., 2023). Importantly, LDL lipid transporters in the CSF are smaller and contain lower levels of lipids in ApoE ε4 carriers (Safieh et al., 2019), and brain tissue analysis of ApoE ε4 carriers show clear impairments in lipid metabolism (Nock et al., 2017).
Therefore, the reason why ApoE ε4 carriers are at risk to develop AD is most likely due to the fact that ApoE ε4 is less able to transport lipids in the brain to compensate for the loss of glucose utilization in neurons. If synapses use lipids/ketones for energy, reduced supplies of ketones by ApoE ε4 will most certainly accelerate synaptic failure and disease progression.
References:
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8(6):429-31. PubMed.
Bailly M, Destrieux C, Hommet C, Mondon K, Cottier JP, Beaufils E, Vierron E, Vercouillie J, Ibazizene M, Voisin T, Payoux P, Barré L, Camus V, Guilloteau D, Ribeiro MJ. Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer's Disease and Mild Cognitive Impairment: MRI and (18)F-FDG PET Quantitative Analysis Using FreeSurfer. Biomed Res Int. 2015;2015:583931. Epub 2015 Jun 17 PubMed.
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921-3. PubMed.
de la Monte SM. Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today?. J Alzheimers Dis. 2024;101(s1):S317-S343. PubMed.
Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, Tai YF, Fox N, Kennedy A, Rossor M, Brooks DJ. Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008 Dec;32(3):412-9. PubMed.
Foley P. Lipids in Alzheimer's disease: A century-old story. Biochim Biophys Acta. 2010 Aug;1801(8):750-3. PubMed.
Makino T, Umegaki H, Suzuki Y, Yanagawa M, Nonogaki Z, Nakashima H, Kuzuya M. Relationship between small cerebral white matter lesions and cognitive function in patients with Alzheimer's disease and amnestic mild cognitive impairment. Geriatr Gerontol Int. 2013 Nov 12; PubMed.
Mosconi L, Berti V, Glodzik L, Pupi A, De Santi S, de Leon MJ. Pre-clinical detection of Alzheimer's disease using FDG-PET, with or without amyloid imaging. J Alzheimers Dis. 2010;20(3):843-54. PubMed.
Nock TG, Chouinard-Watkins R, Plourde M. Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline. Biochim Biophys Acta. 2017 Oct;1862(10 Pt A):1068-1078. Epub 2017 Jul 18 PubMed.
Raut S, Bhalerao A, Powers M, Gonzalez M, Mancuso S, Cucullo L. Hypometabolism, Alzheimer's Disease, and Possible Therapeutic Targets: An Overview. Cells. 2023 Aug 8;12(16) PubMed.
Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target for Alzheimer's disease. BMC Med. 2019 Mar 20;17(1):64. PubMed.
Xu H, Fu J, Mohammed Nazar RB, Yang J, Chen S, Huang Y, Bao T, Chen X. Investigation of the Relationship between Apolipoprotein E Alleles and Serum Lipids in Alzheimer's Disease: A Meta-Analysis. Brain Sci. 2023 Nov 6;13(11) PubMed.
Yassine HN, Solomon V, Thakral A, Sheikh-Bahaei N, Chui HC, Braskie MN, Schneider LS, Talbot K. Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon-like peptide-1 receptor agonists. Alzheimers Dement. 2022 Mar;18(3):478-497. Epub 2021 Oct 14 PubMed.
Yonamine CY, Michalani ML, Moreira RJ, Machado UF. Glucose Transport and Utilization in the Hippocampus: From Neurophysiology to Diabetes-Related Development of Dementia. Int J Mol Sci. 2023 Nov 18;24(22) PubMed.
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