Bridging Integrator 1 (BIN1) Genotypes Mediate Alzheimer’s Disease Risk by Altering Neuronal Degeneration

Wang

et al. 2020

Aging

Self Cite

Higher body mass index (BMI) in late-life has recently been considered as a possible protective factor for Alzheimer's disease (AD), which yet remains conflicting. To test this hypothesis, we have evaluated the crosssectional and longitudinal associations of BMI categories with CSF biomarkers, brain β-amyloid (Aβ) load, brain structure, and cognition and have assessed the effect of late-life BMI on AD risk in a large sample (n = 1,212) of nondemented elderly from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. At baseline, higher latelife BMI categories were associated with higher levels of CSF Aβ42 (p=0.037), lower levels of CSF total-tau (t-tau, p=0.026) and CSF t-tau/Aβ42 (p=0.008), lower load of Aβ in the right hippocampus (p=0.030), as well as larger volumes of hippocampus (p<0.0001), entorhinal cortex (p=0.009) and middle temporal lobe (p=0.040). But no association was found with CSF phosphorylated-tau (p-tau) or CSF p-tau/Aβ42. Longitudinal studies showed that higher BMI individuals experienced a slower decline in cognitive function. In addition, Kaplan-Meier survival analysis revealed that higher late-life BMI had a reduced risk of progression to AD over time (p = 0.009). Higher BMI in late-life decreased the risk of AD, and this process may be driven by AD-related biomarkers.

Section: Mri Scans and Image Processingmentioning

confidence: 97%

Late-life obesity is a protective factor for prodromal Alzheimer’s disease: a longitudinal study

Wang

et al. 2020

Aging

Self Cite

“…The recent identification of Bin1 as a FEME component [28] broadens the possibilities for a link between FEME and neurodegeneration. Bin1 is strongly linked to Alzheimer's disease, but through Tau and amyloid-β pathology [122,123]. As for Endophilin, Bin1 levels are increased in Alzheimer's patients and its depletion suppressed Tau-mediated neurotoxicity [124].…”

Section: Is Feme Involved In Neurodegenerative Diseases?mentioning

confidence: 99%

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

Casamento

Boucrot

2020

Biochemical Journal

108

Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Clathrin-mediated endocytosis (CME) is the housekeeping pathway in resting cells but additional Clathrin-independent endocytic (CIE) routes, including Fast Endophilin-Mediated Endocytosis (FEME), internalize specific cargoes and support diverse cellular functions. FEME is part of the Dynamin-dependent subgroup of CIE pathways. Here, we review our current understanding of the molecular mechanism of FEME. Key steps are: (i) priming, (ii) cargo selection, (iii) membrane curvature and carrier formation, (iv) membrane scission and (v) cytosolic transport. All steps are controlled by regulatory mechanisms mediated by phosphoinositides and by kinases such as Src, LRRK2, Cdk5 and GSK3β. A key feature of FEME is that it is not constitutively active but triggered upon the stimulation of selected cell surface receptors by their ligands. In resting cells, there is a priming cycle that concentrates Endophilin into clusters on discrete locations of the plasma membrane. In the absence of receptor activation, the patches quickly abort and new cycles are initiated nearby, constantly priming the plasma membrane for FEME. Upon activation, receptors are swiftly sorted into pre-existing Endophilin clusters, which then bud to form FEME carriers within 10 s. We summarize the hallmarks of FEME and the techniques and assays required to identify it. Next, we review similarities and differences with other CIE pathways and proposed cargoes that may use FEME to enter cells. Finally, we submit pending questions and future milestones and discuss the exciting perspectives that targeting FEME may boost treatments against cancer and neurodegenerative diseases.

“…AD is a clinically heterogeneous neurodegenerative disease with a strong genetic component. Genetic risk factors of AD impact the CSF or neuroimaging biomarkers through which they might modulate the process of AD [ 5 ]. Thus, biomarkers for AD may be used as endophenotypes to explore the genetic factors that impact their metabolism [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide association study identifies two loci influencing plasma neurofilament light levels

Yuan

et al. 2018

BMC Med Genomics

Self Cite

BackgroundPlasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD.MethodsThis study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model.ResultsThe minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10− 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10− 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018–2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234).ConclusionGWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0364-8) contains supplementary material, which is available to authorized users.