TY  - JOUR
AB  - UNLABELLED: Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00888-z.
AU  - Borkowski, K.*
AU  - Liang, N.*
AU  - Zhao, N.*
AU  - Arnold, M.
AU  - Huynh, K.*
AU  - Karu, N.*
AU  - MahmoudianDehkordi, S.*
AU  - Kueider-Paisley, A.*
AU  - Kanekiyo, T.*
AU  - Bu, G.*
AU  - Kaddurah-Daouk, R.*
C1  - 75454
C2  - 58329
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - APOE genotype influences on the brain metabolome of aging mice - role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype.
JO  - Mol. Neurodegener.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2025
ER  - 

TY  - JOUR
AB  - BACKGROUND: Parkinson's disease (PD) affects millions of people worldwide, but only 5-10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation. METHODS: A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing-whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. RESULTS: The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine-129 phosphorylation. CONCLUSIONS: The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.
AU  - Brücke, C.*
AU  - Al-Azzani, M.*
AU  - Ramalingam, N.*
AU  - Ramón, M.*
AU  - Sousa, R.L.*
AU  - Buratti, F.*
AU  - Zech, M.
AU  - Sicking, K.*
AU  - Amaral, L.A.*
AU  - Gelpi, E.*
AU  - Chandran, A.*
AU  - Agarwal, A.*
AU  - Chaves, S.R.*
AU  - Fernández, C.O.*
AU  - Dettmer, U.*
AU  - Lautenschläger, J.*
AU  - Zweckstetter, M.*
AU  - Busnadiego, R.F.*
AU  - Zimprich, A.*
AU  - Outeiro, T.F.*
C1  - 75639
C2  - 57906
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features.
JO  - Mol. Neurodegener.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2025
ER  - 

TY  - JOUR
AB  - BACKGROUND: The prion-like spreading of Tau pathology is the leading cause of disease progression in various tauopathies. A critical step in propagating pathologic Tau in the brain is the transport from the extracellular environment and accumulation inside naïve neurons. Current research indicates that human neurons internalize both the physiological extracellular Tau (eTau) monomers and the pathological eTau aggregates. However, similarities or differences in neuronal transport mechanisms between Tau species remain elusive. METHOD: Monomers, oligomers, and fibrils of recombinant 2N4R Tau were produced and characterized by biochemical and biophysical methods. A neuronal eTau uptake and accumulation assay was developed for human induced pluripotent stem cell-derived neurons (iPSCNs) and Lund human mesencephalic cells (LUHMES)-derived neurons. Mechanisms of uptake and cellular accumulation of eTau species were studied by using small molecule inhibitors of endocytic mechanisms and siRNAs targeting Tau uptake mediators. RESULTS: Extracellular Tau aggregates accumulated more than monomers in human neurons, mainly due to the higher efficiency of small fibrillar and soluble oligomeric aggregates in intraneuronal accumulation. A competition assay revealed a distinction in the neuronal accumulation between physiological eTau Monomers and pathology-relevant aggregates, suggesting differential transport mechanisms. Blocking heparan sulfate proteoglycans (HSPGs) with heparin only inhibited the accumulation of eTau aggregates, whereas monomers' uptake remained unaltered. At the molecular level, the downregulation of genes involved in HSPG synthesis exclusively blocked neuronal accumulation of eTau aggregates but not monomers, suggesting its role in the transport of pathologic Tau. Moreover, the knockdown of LRP1, as a receptor of Tau, mainly reduced the accumulation of monomeric form, confirming its involvement in Tau's physiological transport. CONCLUSION: These data propose that despite the similarity in the cellular mechanism, the uptake and accumulation of eTau Monomers and aggregates in human neurons are regulated by different molecular mediators. Thus, they address the possibility of targeting the pathological spreading of Tau aggregates without disturbing the probable physiological or non-pathogenic transport of Tau Monomers.
AU  - Marvian, A.T.*
AU  - Strauss, T.*
AU  - Tang, Q.*
AU  - Tuck, B.J.*
AU  - Keeling, S.*
AU  - Rüdiger, D.*
AU  - Mirzazadeh Dizaji, N.*
AU  - Mohammad-Beigi, H.*
AU  - Nuscher, B.*
AU  - Chakraborty, P.*
AU  - Sutherland, D.S.*
AU  - McEwan, W.A.*
AU  - Köglsperger, T.*
AU  - Zahler, S.*
AU  - Zweckstetter, M.*
AU  - Lichtenthaler, S.F.*
AU  - Wurst, W.
AU  - Schwarz, S.*
AU  - Höglinger, G.*
C1  - 72917
C2  - 56795
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons.
JO  - Mol. Neurodegener.
VL  - 19
IS  - 1
PB  - Bmc
PY  - 2024
ER  - 

TY  - JOUR
AB  - BACKGROUND: Major retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and retinal detachment, are associated with a local decrease in oxygen availability causing the formation of hypoxic areas affecting the photoreceptor (PR) cells. Here, we addressed the underlying pathological mechanisms of PR degeneration by focusing on energy metabolism during chronic activation of hypoxia-inducible factors (HIFs) in rod PR. METHODS: We used two-photon laser scanning microscopy (TPLSM) of genetically encoded biosensors delivered by adeno-associated viruses (AAV) to determine lactate and glucose dynamics in PR and inner retinal cells. Retinal layer-specific proteomics, in situ enzymatic assays and immunofluorescence studies were used to analyse mitochondrial metabolism in rod PRs during chronic HIF activation. RESULTS: PRs exhibited remarkably higher glycolytic flux through the hexokinases than neurons of the inner retina. Chronic HIF activation in rods did not cause overt change in glucose dynamics but an increase in lactate production nonetheless. Furthermore, dysregulation of the oxidative phosphorylation pathway (OXPHOS) and tricarboxylic acid (TCA) cycle in rods with an activated hypoxic response decelerated cellular anabolism causing shortening of rod photoreceptor outer segments (OS) before onset of cell degeneration. Interestingly, rods with deficient OXPHOS but an intact TCA cycle did not exhibit these early signs of anabolic dysregulation and showed a slower course of degeneration. CONCLUSION: Together, these data indicate an exceeding high glycolytic flux in rods and highlight the importance of mitochondrial metabolism and especially of the TCA cycle for PR survival in conditions of increased HIF activity.
AU  - Todorova, V.*
AU  - Stauffacher, M.F.*
AU  - Ravotto, L.*
AU  - Nötzli, S.*
AU  - Karademir, D.*
AU  - Ebner, L.J.A.*
AU  - Imsand, C.*
AU  - Merolla, L.*
AU  - Hauck, S.M.
AU  - Samardzija, M.*
AU  - Saab, A.S.*
AU  - Barros, L.F.*
AU  - Weber, B.*
AU  - Grimm, C.*
C1  - 67553
C2  - 54064
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Deficits in mitochondrial TCA cycle and OXPHOS precede rod photoreceptor degeneration during chronic HIF activation.
JO  - Mol. Neurodegener.
VL  - 18
IS  - 1
PB  - Bmc
PY  - 2023
ER  - 

TY  - JOUR
AB  - Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer's disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in thePLCG2gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plc gamma 2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plc gamma 2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLC gamma 2-P522R, but not in PLC gamma 2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plc gamma 2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plc gamma 2-P522R KI mice. Conclusion The AD-associated protective Plc gamma 2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLC gamma 2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.
AU  - Takalo, M.*
AU  - Wittrahm, R.*
AU  - Wefers, B.
AU  - Parhizkar, S.*
AU  - Jokivarsi, K.*
AU  - Kuulasmaa, T.*
AU  - Mäkinen, P.*
AU  - Martiskainen, H.*
AU  - Wurst, W.
AU  - Xiang, X.*
AU  - Marttinen, M.*
AU  - Poutiainen, P.*
AU  - Haapasalo, A.*
AU  - Hiltunen, M.*
AU  - Haass, C.*
C1  - 60071
C2  - 49209
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The Alzheimer's disease-associated protective Plc gamma 2-P522R variant promotes immune functions.
JO  - Mol. Neurodegener.
VL  - 15
IS  - 1
PB  - Bmc
PY  - 2020
ER  - 

TY  - JOUR
AB  - Background: The R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) significantly increases the risk for late onset Alzheimer's disease. Mouse models accurately reproducing phenotypes observed in Alzheimer' disease patients carrying the R47H coding variant are required to understand the TREM2 related dysfunctions responsible for the enhanced risk for late onset Alzheimer's disease.Methods: A CRISPR/Cas9-assisted gene targeting strategy was used to generate Trem2 R47H knock-in mice. Trem2 mRNA and protein levels as well as Trem2 splicing patterns were assessed in these mice, in iPSC-derived human microglia-like cells, and in human brains from Alzheimer's patients carrying the TREM2 R47H risk factor.Results: Two independent Trem2 R47H knock-in mouse models show reduced Trem2 mRNA and protein production. In both mouse models Trem2 haploinsufficiency was due to atypical splicing of mouse Trem2 R47H, which introduced a premature stop codon. Cellular splicing assays using minigene constructs demonstrate that the R47H variant induced abnormal splicing only occurs in mice but not in humans. TREM2 mRNA levels and splicing patterns were both normal in iPSC-derived human microglia-like cells and patient brains with the TREM2 R47H variant.Conclusions: The Trem2 R47H variant activates a cryptic splice site that generates miss-spliced transcripts leading to Trem2 haploinsufficiency only in mice but not in humans. Since Trem2 R47H related phenotypes are mouse specific and do not occur in humans, humanized TREM2 R47H knock-in mice should be generated to study the cellular consequences caused by the human TREM2 R47H coding variant. Currently described phenotypes of Trem2 R47H knock-in mice can therefore not be translated to humans.
AU  - Xiang, X.*
AU  - Piers, T.M.*
AU  - Wefers, B.
AU  - Zhu, K.*
AU  - Mallach, A.*
AU  - Brunner, B.*
AU  - Kleinberger, G.*
AU  - Song, W.*
AU  - Colonna, M.*
AU  - Herms, J.*
AU  - Wurst, W.
AU  - Pocock, J.M.*
AU  - Haass, C.*
C1  - 54329
C2  - 45509
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The Trem2 R47H Alzheimer's risk variant impairs splicing and reduces Trem2 mRNA and protein in mice but not in humans.
JO  - Mol. Neurodegener.
VL  - 13
IS  - 1
PB  - Bmc
PY  - 2018
ER  - 

TY  - JOUR
AB  - Background: The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer's disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L. Methods and results: We generated antibodies against SEZ6 and SEZ6L and validated these proteins as BACE1 substrates in vitro and in vivo. Levels of the soluble, BACE1-cleaved ectodomain of both proteins (sSEZ6, sSEZ6L) were strongly reduced upon BACE1 inhibition in primary neurons and also in vivo in brains of BACE1-deficient mice. BACE1 inhibition increased neuronal surface levels of SEZ6 and SEZ6L as shown by cell surface biotinylation, demonstrating that BACE1 controls surface expression of both proteins. Moreover, mass spectrometric analysis revealed that the BACE1 cleavage site in SEZ6 is located in close proximity to the membrane, similar to the corresponding cleavage site in SEZ6L. Finally, an improved method was developed for the proteomic analysis of murine cerebrospinal fluid (CSF) and was applied to CSF from BACE-deficient mice. Hereby, SEZ6 and SEZ6L were validated as BACE1 substrates in vivo by strongly reduced levels in the CSF of BACE1-deficient mice. Conclusions: This study demonstrates that SEZ6 and SEZ6L are physiological BACE1 substrates in the murine brain and suggests that sSEZ6 and sSEZ6L levels in CSF are suitable markers to monitor BACE1 inhibition in mice.
AU  - Pigoni, M.*
AU  - Wanngren, J.*
AU  - Kuhn, P.-H.*
AU  - Munro, K.M.*
AU  - Gunnersen, J.M.*
AU  - Takeshima, H.*
AU  - Feederle, R.
AU  - Voytyuk, I.*
AU  - de Strooper, B.*
AU  - Levasseur, M.D.*
AU  - Hrupka, B.J.*
AU  - Mueller, S.A.*
AU  - Lichtenthaler, S.F.*
C1  - 49817
C2  - 40970
CY  - London
TI  - Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons.
JO  - Mol. Neurodegener.
VL  - 11
PB  - Biomed Central Ltd
PY  - 2016
ER  - 

TY  - JOUR
AB  - BACKGROUND/PURPOSE OF THE STUDY: Epidemiological evidence suggests that low doses of ionising radiation (≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration. RESULTS: Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6-7 months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134). Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFα indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy. CONCLUSION: These data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices.
AU  - Kempf, S.J.
AU  - Casciati, A.*
AU  - Buratovic, S.*
AU  - Janik, D.
AU  - von Toerne, C.
AU  - Ueffing, M.
AU  - Neff, F.
AU  - Mörtl, S.
AU  - Stenerlöw, B.*
AU  - Saran, A.*
AU  - Atkinson, M.J.
AU  - Eriksson, P.*
AU  - Pazzaglia, S.*
AU  - Tapio, S.
C1  - 43044
C2  - 35964
TI  - The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammation.
JO  - Mol. Neurodegener.
VL  - 9
PY  - 2014
ER  - 

TY  - JOUR
AB  - BACKGROUND: Prion diseases such as bovine spongiform encephalopathies (BSE) are transmissible neurodegenerative diseases which are presumably caused by an infectious conformational isoform of the cellular prion protein. Previous work has provided evidence that in murine prion disease the endogenous retrovirus (ERV) expression is altered in the brain. To determine if prion-induced changes in ERV expression are a general phenomenon we used a non-human primate model for prion disease. RESULTS: Cynomolgus macaques (Macaca fasicularis) were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. We could show that Class I gammaretroviruses HERV-E4-1, ERV-9, and MacERV-4 increase expression in BSE-infected macaques. In a second approach, we analysed ERV-K-(HML-2) RNA and protein expression in extracts from the same cynomolgus macaques. Here we found a significant downregulation of both, the macaque ERV-K-(HML-2) Gag protein and RNA in the frontal/parietal cortex of BSE-infected macaques. CONCLUSIONS: We provide evidence that dysregulation of ERVs in response to BSE-infection can be detected on both, the RNA and the protein level. To our knowledge, this is the first report on the differential expression of ERV-derived structural proteins in prion disorders. Our findings suggest that endogenous retroviruses may induce or exacerbate the pathological consequences of prion-associated neurodegeneration.
AU  - Greenwood, A.D.*
AU  - Vincendeau, M.
AU  - Schmädicke, A.C.*
AU  - Montag, J.*
AU  - Seifarth, W.*
AU  - Motzkus, D.*
C1  - 6544
C2  - 28856
TI  - Bovine spongiform encephalopathy infection alters endogenous retrovirus expression in distinct brain regions of cynomolgus macaques (Macaca fascicularis).
JO  - Mol. Neurodegener.
VL  - 6
IS  - 1
PB  - Biomed Central Ltd.
PY  - 2011
ER  -