Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer’s disease

Essayan-Perez, Sofia; Südhof, Thomas C.

doi:10.1016/j.neuron.2023.07.005

Cited by 14 publications

(6 citation statements)

References 111 publications

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“…Our finding corresponds to the Nielsen et al recent metabolomic study, demonstrating that histidine metabolisms are downregulated in patients with AD [ 51 ]. Assuming that Bacteroidia may contribute to the downregulation of HISTSYN-PWY and that the latter is associated with the decrease in cholesterol level, which is known as a risk factor and the main culprit of AD [ 52 , 53 , 54 ], obtained results may be used in further new treatment target-searching studies. Existent data on the L-lysine biosynthesis II pathway reveal the twofold function of lysine in human health.…”

Section: Discussionmentioning

confidence: 99%

Oral Microbiome Stamp in Alzheimer’s Disease

Issilbayeva,

Kaiyrlykyzy,

Vinogradova

et al. 2024

Pathogens

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Recent studies have suggested that periodontal disease and alterations in the oral microbiome may be associated with cognitive decline and Alzheimer’s disease (AD) development. Here, we report a case-control study of oral microbiota diversity in AD patients compared to healthy seniors from Central Asia. We have characterized the bacterial taxonomic composition of the oral microbiome from AD patients (n = 64) compared to the healthy group (n = 71) using 16S ribosomal RNA sequencing. According to our results, the oral microbiome of AD has a higher microbial diversity, with an increase in Firmicutes and a decrease in Bacteroidetes in the AD group. LEfSe analysis showed specific differences at the genus level in both study groups. A region-based analysis of the oral microbiome compartment in AD was also performed, and specific differences were identified, along with the absence of differences in bacterial richness and on the functional side. Noteworthy findings demonstrated the decrease in periodontitis-associated bacteria in the AD group. Distinct differences were revealed in the distribution of metabolic pathways between the two study groups. Our study confirms that the oral microbiome is altered in AD. However, a comprehensive picture of the complete composition of the oral microbiome in patients with AD requires further investigation.

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Section: Discussionmentioning

confidence: 99%

Oral Microbiome Stamp in Alzheimer’s Disease

Issilbayeva,

Kaiyrlykyzy,

Vinogradova

et al. 2024

Pathogens

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“…19,20 Further studies have shown that genetic mutations or polymorphisms involved in brain cholesterol Cholesterol not only serves as a key structural component of cell membranes and myelin but also is a precursor for the synthesis of steroid hormones and bile acids, as well as a necessary substance for the formation of synapses and dendrites. 22 Additionally, cholesterol affects cell function through its biologically active oxidized products, oxysterols. Therefore, cholesterol is important for the physiological functions of neurons.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression‐like behaviors in 5xFAD mice

Gong,

Li,

Liu

et al. 2024

Anim Models and Exp Med

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BackgroundApolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for late‐onset Alzheimer's disease, and it can aggravate depressive symptoms in non‐AD patients. However, the impact of ApoE4 on AD‐associated depression‐like behaviors and its underlying pathogenic mechanisms remain unclear.MethodsThis study developed a 5xFAD mouse model overexpressing human ApoE4 (E4FAD). Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice. Changes in peripheral and central lipid metabolism, as well as the levels of serotonin (5‐HT) and γ‐aminobutyric acid (GABA) neurotransmitters in the prefrontal cortex, were examined. In addition, the protein levels of 24‐dehydrocholesterol reductase/glycogen synthase kinase‐3 beta/mammalian target of rapamycin (DHCR24/GSK3β/mTOR) and postsynaptic density protein 95/calmodulin‐dependent protein kinase II/brain‐derived neurotrophic factor (PSD95/CaMK‐II/BDNF) were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.ResultsCompared with 5xFAD mice, E4FAD mice exhibited more severe depression‐like behaviors and cognitive impairments. These mice also exhibited increased amyloid‐beta deposition in the hippocampus, increased astrocyte numbers, and decreased expression of depression‐related neurotransmitters 5‐HT and GABA in the prefrontal cortex. Furthermore, lipid metabolism disorders were observed in E4FAD, manifesting as elevated low‐density lipoprotein cholesterol and reduced high‐density lipoprotein cholesterol in peripheral blood, decreased cholesterol level in the prefrontal cortex, and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis. Abnormal expression of proteins related to the DHCR24/GSK3β/mTOR and PSD95/CaMK‐II/BDNF pathways was also observed.ConclusionThis study found that ApoE4 overexpression exacerbates depression‐like behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice. The mechanism may involve the induction of central and peripheral lipid metabolism disorders. Therefore, modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression. This study also provided a better animal model for studying AD comorbid with depression.

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“…In addition, PI(4,5)P2 was recently shown to regulate synaptic vesicle endocytosis downstream of synaptotagmin-1 at the plasma membrane 89 . Finally, cholesterol regulation was shown to be important broadly for regulating synapse number and function, through a process that may be dysregulated in Alzheimer's disease 90 . Together these data indicate that membrane lipid composition is a critical, conserved, and perhaps overlooked mediator of synaptic development and function.…”

Section: An Intracellular Mechanism For Presynaptic Assemblymentioning

confidence: 99%

Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules

Frankel,

Tiroumalechetty,

Henry

et al. 2023

Preprint

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Textbook models of synaptogenesis position cell adhesion molecules such as neurexin as initiators of synapse assembly. Here we discover a mechanism for presynaptic assembly that occurs prior to neurexin recruitment, while supporting a role for neurexin in synapse maintenance. We find that the cytosolic active zone scaffold SYD-1 interacts with membrane phospholipids to promote active zone protein clustering at the plasma membrane, and subsequently recruits neurexin to stabilize those clusters. Employing molecular dynamics simulations to model intrinsic interactions between SYD-1 and lipid bilayers followed byin vivotests of these predictions, we find that PIP2-interacting residues in SYD-1’s C2 and PDZ domains are redundantly necessary for proper active zone assembly. Finally, we propose that the uncharacterized yet evolutionarily conserved short γ isoform of neurexin represents a minimal neurexin sequence that can stabilize previously assembled presynaptic clusters, potentially a core function of this critical protein.

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Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer’s disease

Cited by 14 publications

References 111 publications

Oral Microbiome Stamp in Alzheimer’s Disease

Oral Microbiome Stamp in Alzheimer’s Disease

Apolipoprotein E4 interferes with lipid metabolism to exacerbate depression‐like behaviors in 5xFAD mice

Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules

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