Sci Transl Med︱New Discovery!

Author ︱ Fu Huimin, editor in charge ︱ Wang Sizhen Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly.
It has a strong genetic component [1]
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Previous studies have found that there is a mutation in the amyloid precursor protein gene (APP) that prevents AD dementia (APP-A673T), and it has a profound function in reducing the production of amyloid (Aβ) [2], which indicates the onset of disease There may also be protective mutations in the core genes of the mechanism to prevent the occurrence of diseases
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Therefore, identifying genetic factors that protect dementia and promote healthy brain aging may provide help for the etiology of the disease and drug targeting strategies
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 The alleles of the apolipoprotein E (APOE) gene are the main genetic risk factors for AD and Lewy body dementia (DLB), and APOE2 can prevent the occurrence of AD and DLB [3, 4]
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Recently, studies have found that APOE3 mutations may be resistant to autosomal dominant AD by reducing the interaction between APOE and heparin [5]
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Bu Guojun’s research team also found that the APOE3-V236E mutation has a protective effect on AD dementia [6], but the mechanism of this mutation to prevent AD risk is still unclear
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 Recently, Chia-Chen Liu (first author and corresponding author) and Bu Guojun (corresponding author) of the Mayo Clinic in the United States published an online publication on Science Translational Medicine entitled "APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia" research paper
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Through human genetic and pathological analysis and functional analysis in cell and animal models, the research team proved that the APOE3-Jacksonville (V236E) variant can promote the aging of healthy brains, reduce Aβ by reducing APOE self-association and increasing lipidation And found that this gene mutation can improve Aβ-related APOE production, plaque load and toxicity
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This study reveals that APOE aggregation is of great significance in the pathogenesis of AD and DLB, and provides insights for the development of treatment strategies for APOE aggregation in dementia patients
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The research team previously discovered the APOE3-Jacksonville (V236E) variant (hereinafter referred to as APOE3-Jac) in AD patients (Figure 1A), which reduces the risk of AD [6]
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So, the question is, what is its potential protective mechanism? Different from the brains of AD patients, the brains of patients with APOE3-Jac variants (>85 years old) show normal structure, Aβ-negative, and neurodegenerative-negative (Figure 1B, C)
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In the brains of APOE3 and APOE3-Jac carriers, there was no difference in the level of soluble APOE; the levels of insoluble APOE in the brain tissue of APOE3-Jac carriers were significantly reduced, and the ratio of soluble/insoluble APOE increased (Figure 1D, E), which indicates that APOE variants may have the function of reducing protein aggregation
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In addition, the contents of soluble Aβ42, insoluble Aβ40 and Aβ42 in the brains of carriers of this mutation were significantly reduced (Figure 1F, G)
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Immunohistochemistry found that there are typical core dense Aβ plaques in APOE3 brains, while APOE3-jac mutant brains have some diffuse, amorphous Aβ deposits, or no plaque pathology (Figure 1H)
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These results indicate that the self-aggregation of APOE may promote the accumulation and deposition of Aβ
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In other words, the reduction of APOE accumulation in APOE3-Jac carriers may be a key mechanism for its protective effect on the development of AD
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Figure 1 APOE aggregation and insoluble Aβ reduction in the brain of APOE3-Jac vector (Source: Liu et al.
, Sci Transl Med, 2021) So, how does the APOE3-Jac mutation affect APOE3 aggregation? The authors found that the APOE3-Jac variant is located near the lipid binding region of APOE3 and also in the APOE oligomerization region (Figure 2A)
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First, the results of molecular exclusion chromatography and molecular crosslinking showed that wild-type APOE3 mainly exists in the form of oligomers, while APOE3-jac is mainly in the form of monomers (Figure 2B-D)
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Secondly, considering that the regions involved in APOE self-aggregation overlap with the lipid binding regions, they tested the lipid loading characteristics of APOE3 and APOE3-Jac variants, and found that compared with APOE3, APOE3-Jac variants are more effective in promoting cholesterol efflux.
Effective (Figure 2E, F)
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In order to evaluate whether this mutation is also related to the more abundant cholesterol in the human brain, the researchers immunoprecipitated APOE under natural conditions and found that the cholesterol-APOE ratio in the APOE3-jac mutant brain was higher than that in the APOE3 brain (Figure 2G)
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These results indicate that APOE3-jac variants can reduce APOE self-aggregation and increase lipidation
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Figure 2 APOE3-Jac mutation reduces APOE aggregation and enhances lipid binding (Source: Liu et al.
, Sci Transl Med, 2021) In order to study whether APOE3-Jac mutation affects the pathogenesis of Aβ in vivo, the research team approved AAV-mediated gene delivery established 5xFAD Aβ model mice expressing APOE3 or APOA3-Jac
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They found that compared with mice expressing AAV-APOE3, mice expressing AAV-APOE3-Jac had significantly reduced Aβ deposition, insoluble Aβ40 and Aβ42, and fibrous plaque load (Figure 3A-C), which was associated with Aβ plaques.
APOE and microglia aggregation were also significantly reduced (Figure 3D, E); regression analysis showed that APOE related to plaques was positively correlated with the load of amyloid plaques and the number of microglia around the plaques (Figure 3F, G) ; Dystrophic neurites around amyloid plaques are also significantly reduced, and plaque-related neuroinflammatory dystrophy is positively correlated with the level of APOE (Figure 3H, I)
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This result indicates that APOE3, which is plaque-related, but not APOE3-Jac, promotes Aβ deposition and related neurotoxicity
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Figure 3 APOE3-Jac mutation reduces Aβ deposition and plaque-related toxicity in amyloid model mice (Source: Liu et al.
, Sci Transl Med, 2021) APOE4 is the strongest genetic risk factor for late-onset AD.
Therefore, the research team further understood the aggregation status of APOE4 in AD
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First, they found that the increased tendency of APOE4 to accumulate may promote the accumulation and deposition of Aβ in AD
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So can the mutation of APOE4-Jac (V2346E) change the aggregation characteristics of APOE4? So they tested the molecular size of wild-type APOE4 and APOE4-Jac.
The results of molecular exclusion chromatography and cross-linking analysis showed that wild-type APOE4 mainly exists as oligomers, while APOE4-Jac mainly exists as monomers, and a few are oligomers.
The existence of objects (Figure 4A-C), this result is also consistent with the author's previous results (Figure 2 BD)
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Cross-linking analysis also showed that APOE4-Jac has a low affinity for heparin, and APOE4-Jac aggregation is also reduced (Figure 4D-F)
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In addition, the co-expression of APOE3-Jac and APOE4 in cells can slow down the oligomerization characteristics of APOE4
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Figure 4 APOE4-Jac (V2346E) mutation can reduce APOE4 aggregation (Source: Liu et al.
, Sci Transl Med, 2021) Conclusion and discussion, inspiration and outlook In general, this study shows that APOE3-Jac mutation By reducing its own aggregation, then reducing amyloid plaques and related toxicity, and promoting lipidation, so as to protect AD and related dementia
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This study reveals the potential pathogenic mechanism of APOE aggregation and plaque-related microglia response and neurotoxicity, which are of great significance to the pathogenesis of APOE-related diseases and the design of mechanism-based APOE targeted therapies
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 This study still has several limitations: First, although the study has proved the key role of APOE3-Jac in the regulation of Aβ pathology; however, whether APOE3-Jac affects tau disease and tau protein-mediated neurotoxicity needs further research
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Secondly, this study used astrocyte-specific promoters to express APOE3 or APOE3-Jac.
However, most of the APOE in the brain is produced in astrocytes, and recently it has also been found in normal aging and AD pathological microglia.
The expression of APOE in cells is significantly up-regulated [7], so future research should explore the role of APOE3-Jac in other brain cell types (such as microglia)
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Third, due to the relatively low frequency of APOE3-Jac mutations and the small sample size of the human study in this study, the next need to be explored in a larger or independent cohort
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Original link: https:// Selected previous articles [1] PNAS | Breakthrough! Optogenetic stimulation of the midbrain wedge-shaped nucleus regulates the motor function of Parkinson’s disease mice [2] PNAS︱ Tan Hongtao/Chen Peng's research group collaborated to reveal that dopaminergic neurons regulate chronic stress-induced memory impairment in Drosophila [3] Mol Psychiatry | Gao Tianming The research team revealed the local neural network mechanism of fear memory fading [4] Nat Commun | Working memory representation of the visual cortex regulates the effect of distracting attention [5] Science | Breakthrough! Immune CD4+ T cells are involved in the disease process of Lewy body dementia [6] Cell Rep︱ New research reveals the role of hypothalamic neuronal calcium homeostasis regulators in the formation of obesity [7] Science︱ first confirmed in humans: multiple neurodegeneration Sexual diseases can affect the neurogenesis of the hippocampal dentate gyrus [8] Neuron︱ new discovery! Hippocampal playback in the awake state promotes memory function by storing and updating specific past experiences [9] Mol Psychiatry︱ A new discovery of biomarkers for depression-mitochondrial proteins in exosomes [10] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [11] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional spatial heterogeneity of the cerebellar nucleus to the thalamus.
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Guo, D.
Zhang, Y.
Zeng, TY Huang, H.
Xu, Y.
Zhao, Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.
Mol.
Neurodegener.
15, 40 (2020).
2, T.