Alzheimer’s disease: insights from a network medicine perspective

Conte, Federica; Paci, Paola

doi:10.1038/s41598-022-20404-3

Cited by 4 publications

(1 citation statement)

References 50 publications

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“…Recent network-based approach studies have revealed that upregulation of SHIP2 (SH2 domain-containing Inositol 5-Phosphatase 2) transcripts encoded by INPPL1 (Inositol Polyphosphate Phosphatase Like 1) is significantly associated with cognitive decline and neuropathological lesions in human AD and aging brains [ 65 ] and that INPPL1 is one of the most significant AD-associated genes that can be potential diagnostic biomarkers and therapeutic targets for AD [ 24 ]. SHIP2 is one of the ten PI 5-phosphatases identified in the human genome [ 72 ].…”

Section: Introductionmentioning

confidence: 99%

Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression

Ando,

Küçükali,

Doeraene

et al. 2024

Acta Neuropathol

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A recent large genome-wide association study has identified EGFR (encoding the epidermal growth factor EGFR) as a new genetic risk factor for late-onset AD. SHIP2, encoded by INPPL1, is taking part in the signalling and interactome of several growth factor receptors, such as the EGFR. While INPPL1 has been identified as one of the most significant genes whose RNA expression correlates with cognitive decline, the potential alteration of SHIP2 expression and localization during the progression of AD remains largely unknown. Here we report that gene expression of both EGFR and INPPL1 was upregulated in AD brains. SHIP2 immunoreactivity was predominantly detected in plaque-associated astrocytes and dystrophic neurites and its increase was correlated with amyloid load in the brain of human AD and of 5xFAD transgenic mouse model of AD. While mRNA of INPPL1 was increased in AD, SHIP2 protein undergoes a significant solubility change being depleted from the soluble fraction of AD brain homogenates and co-enriched with EGFR in the insoluble fraction. Using FRET-based flow cytometry biosensor assay for tau-tau interaction, overexpression of SHIP2 significantly increased the FRET signal while siRNA-mediated downexpression of SHIP2 significantly decreased FRET signal. Genetic association analyses suggest that some variants in INPPL1 locus are associated with the level of CSF pTau. Our data support the hypothesis that SHIP2 is an intermediate key player of EGFR and AD pathology linking amyloid and tau pathologies in human AD.

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Section: Introductionmentioning

confidence: 99%

Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression

Ando,

Küçükali,

Doeraene

et al. 2024

Acta Neuropathol

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Integrated network pharmacology and comprehensive bioinformatics identifying the mechanisms and molecular targets of Jieyu Anshen Granules for treating comorbidity with Alzheimer's disease and depression

Ren,

Wen,

et al. 2024

Arabian Journal of Chemistry

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Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer’s disease

Branciamore,

Gogoshin,

Rodin

et al. 2024

Sci Rep

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While there are currently over 40 replicated genes with mapped risk alleles for Late Onset Alzheimer’s disease (LOAD), the Apolipoprotein E locus E4 haplotype is still the biggest driver of risk, with odds ratios for neuropathologically confirmed E44 carriers exceeding 30 (95% confidence interval 16.59–58.75). We sought to address whether the APOE E4 haplotype modifies expression globally through networks of expression to increase LOAD risk. We have used the Human Brainome data to build expression networks comparing APOE E4 carriers to non-carriers using scalable mixed-datatypes Bayesian network (BN) modeling. We have found that VGF had the greatest explanatory weight. High expression of VGF is a protective signal, even on the background of APOE E4 alleles. LOAD risk signals, considering an APOE background, include high levels of SPECC1L, HLA-DRA and RANBP3L. Our findings nominate several new transcripts, taking a combined approach to network building including known LOAD risk loci.

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Alzheimer’s disease: insights from a network medicine perspective

Cited by 4 publications

References 50 publications

Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression

Alteration of gene expression and protein solubility of the PI 5-phosphatase SHIP2 are correlated with Alzheimer’s disease pathology progression

Integrated network pharmacology and comprehensive bioinformatics identifying the mechanisms and molecular targets of Jieyu Anshen Granules for treating comorbidity with Alzheimer's disease and depression

Changes in expression of VGF, SPECC1L, HLA-DRA and RANBP3L act with APOE E4 to alter risk for late onset Alzheimer’s disease

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