Increasing evidence supports that cellular dysregulations in the degradative routes contribute to the initiation and progression of neurodegenerative diseases, including Alzheimer’s disease. Autophagy and endolysosomal homeostasis need to be maintained throughout life as they are major cellular mechanisms involved in both the production of toxic amyloid peptides and the clearance of misfolded or aggregated proteins. As such, alterations in endolysosomal and autophagic flux, as a measure of degradation activity in these routes or compartments, may directly impact as well on disease-related mechanisms such as amyloid-β clearance through the blood-brain-barrier and the interneuronal spreading of amyloid-β and/or Tau seeds, affecting synaptic function, plasticity and metabolism. The emerging of several genetic risk factors for late-onset Alzheimer’s disease that are functionally related to endocytic transport regulation, including cholesterol metabolism and clearance, supports the notion that in particular the autophagy/lysosomal flux might become more vulnerable during ageing thereby contributing to disease onset. In this review we discuss our current knowledge of the risk genes APOE4, BIN1, CD2AP, PICALM, PLD3 and TREM2 and their impact on endolysosomal (dys)regulations in the light of late-onset Alzheimer’s disease pathology. Electronic supplementary material The online version of this article (10.1186/s13024-019-0323-7) contains supplementary material, which is available to authorized users.

After its discovery in 2000, the notion grew that neuroglobin, a neuronal specific heme protein, is involved in cytoprotection. To date, neuroglobin levels have been positively correlated with a beneficial outcome in a plethora of neurotoxic insults, e.g., ischemic and traumatic brain injuries and Alzheimer's disease. The first part of this review goes further into these changes of neuroglobin expression upon different neuronal insults as well as the underlying regulation. In the second part, we shed light on the mechanisms by which neuroglobin contributes to neuroprotection, being (i) the scavenging and detoxification of reactive oxygen/nitrogen species, (ii) the augmentation of the threshold for apoptosis initiation, (iii) its contribution to an anti-inflammatory milieu, and (iv) tissue regeneration. We also consider different neuroglobin models to address as yet unanswered questions. Based on the recent findings and progress in the field, we invigorate the avenues of neuroglobin in neurological ailments to increase in the coming years.

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Neuroglobin (Ngb) is an evolutionary conserved member of the globin family with a primary expression in neurons of which the exact functions remain elusive. A plethora of in vivo and in vitro model systems has been generated to this day to determine the functional biological roles of Ngb. Here, we provide a comprehensive overview and discussion of the different Ngb models, covering animal and cellular models of both overexpression and knockout strategies. Intriguingly, an in-depth literature search of available Ngb expression models revealed crucial discrepancies in the outcomes observed in different models. Not only does the level of Ngb expression—either physiologically, overexpressed, or downregulated—alter its functional properties, the experimental setup, being in vitro or in vivo, does impact the functional outcome as well and, hence, whether or not a physiological and/or therapeutic role is ascribed to Ngb. These differences could highlight either technical or biological adaptations and should be considered until elucidation of the Ngb biology.

Neuroglobin is a heme protein of which increased levels provide neuroprotection against amyloid proteinopathy and hemorrhagic damage. These cellular stressors involve the promotion of ferroptosis—an iron-dependent, lipid peroxide-accreting form of cell death. Hence, we questioned whether neuroglobin could oppose ferroptosis initiation. We detected human neuroglobin (hNgb)-EGFP-expressing SH-SY5Y cells to be significantly more resistant to ferroptosis induction, identifying 0.68-fold less cell death. To elucidate the underlying pathways, this study investigated hNgb-protein interactions with a Co-IP-MS/MS approach both under a physiological and a ferroptotic condition. hNgb binds to proteins of the cellular iron metabolism (e.g., RPL15 and PCBP3) in an unstressed condition and shows an elevated binding ratio towards cell death-linked proteins, such as HNRNPA3, FAM120A, and ABRAXAS2, under ferroptotic stress. Our data also reveal a constitutive interaction between hNgb and the longevity-associated heterodimer XRCC5/XRCC6. Disentangling the involvement of hNgb and its binding partners in cellular processes, using Ingenuity Pathway Analysis, resulted in the integration of hNgb in the ubiquitination pathway, mTOR signaling, 14-3-3-mediated signaling, and the glycolysis cascade. We also detected a previously unknown strong link with motor neuropathies. Hence, this study contributes to the elucidation of neuroglobin’s involvement in cellular mechanisms that provide neuroprotection and the upkeep of homeostasis.

The introduction of tissue engineering has allowed scientists to push the boundaries and treat seriously damaged ocular surface epithelia. They have managed to do this through the development of biological substitutes that restore, maintain or improve tissue function. To ensure the generation of a therapeutically safe and effective graft, knowledge on the transcriptional profile of native and cultured ocular surface epithelia is of undeniable value. Gene expression studies are, however, only as reliable as their proper selection of internal reaction controls or reference genes. In this study, we determined the expression stability of a number of reference genes: 18s rRNA, ACTB, ATP5B, CyC1, EIF4A2, GAPDH, RPL13A, SDHA, TOP1, UBC, and YWHAZ in primary isolates as well as in ex vivo cultured ocular surface epithelia explants (day 0 and/or day 14). Expression stability of the reference genes was assessed with both the geNorm and NormFinder software that use a pairwise comparison and a model-based approach, respectively. Our results extend the general recommendation of using multiple reference genes for normalization purposes to our model systems and provide an overview of several references genes that are likely to be stable in similar culture protocols.

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