EC Neurology

The evolutionarily conserved tumor suppressor gene MEN1 (multiple endocrine neoplasia type 1) and its encoded protein menin, have recently been shown to regulate cholinergic synapse formation in both vertebrates and invertebrates. Moreover, its knockout in adult animals results in learning/memory deficits and depressive-like behaviors in rodent models in a manner analogous to that of the Alzheimer. However, menin’s presence has not been demonstrated in the human brain, nor has its characterization been documented in the neurodegenerative model. In this study, we sought to document the presence of menin, synaptophysin, postsynaptic density protein-95 (PSD-95), nicotinic acetylcholine receptors (nAChRs) and tau in autopsied human tissue obtained from controls followed by the examination of menin’s expression patterns in the Alzheimer disease (AD) individuals. We used frozen tissue obtained from Calgary Brain Bank, controls (n = 6) and AD (n = 6). Optimized immunohistochemistry protocols were used to define the patterns of co-expression of menin with AD marker, tau. For the first time, our data document menin immunoreactivity in human brain and demonstrate its localization patterns in the controls and AD human brains. Moreover, we demonstrate that in the human hippocampus, menin expression is likely perturbed in the AD group. Further investigation is required to determine if perturbation of menin function may underlie nicotinic receptor dysfunction mediating learning and memory deficit in the AD brain.

Keywords: C-Menin; Tau; PSD-95; Synaptophysin; nAChR; MAP2; Alzheimer’s Disease

1. Hou Y., et al. “Ageing as a risk factor for neurodegenerative disease”. Nature Reviews. Neurology10 (2019): 565-581.
2. Viola, K. L., et al. “Why Alzheimer’s is a disease of memory: The attack on synapses by Aß oligomers (ADDLs)”. The Journal of Nutrition Health and AgingS1 (2019).
3. Skaper SD., et al. “Synaptic Plasticity, Dementia and Alzheimer Disease”. CNS and Neurological Disorders - Drug Targets3 (2017): 220-233.
4. Tampellini D. “Synaptic activity and Alzheimer’s disease: A critical update”. Frontiers in Neuroscience (2015): 9.
5. Toumane A., et al. “Differential hippocampal and cortical cholinergic activation during the acquisition, retention, reversal and extinction of a spatial discrimination in an 8-arm radial maze by mice”. Behavioural Brain Research3 (1988): 225-234.
6. Teipel S., et al. “Cholinergic System Imaging in the Healthy Aging Process and Alzheimer Disease”. Encyclopedia of Neuroscience (2009): 857-868.
7. Oz M., et al. “On the interaction of β-amyloid peptides and α7-nicotinic acetylcholine receptors in Alzheimer's disease”. Current Alzheimer Research6 (2013): 618-630.
8. Wang HY., et al. “Beta-amyloid (1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology”. Journal of Biological Chemistry 275 (2000): 5626-5632.
9. Fabiani C and Antollini SS. “Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts”. Frontiers in Cellular Neuroscience 13 (2019): 309.
10. Schindowski K., et al. “Neurotrophic factors in Alzheimer's disease: role of axonal transport”. Genes, Brain, and Behavior1-1 (2008): 43-56.
11. Lima Giacobbo B., et al. “Brain -Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation”. Molecular Neurobiology5 (2019): 3295-3312.
12. Willis BA., et al. “Central pharmacodynamic activity of solanezumab in mild Alzheimer’s disease dementia”. Alzheimers and Dementia: Translational Research and Clinical Interventions 4 (2018): 652-660.
13. Getz AM., et al. “Two proteolytic fragments of menin coordinate the nuclear transcription and postsynaptic clustering of neurotransmitter receptors during synaptogenesis between Lymnaea neurons”. Scientific Reports 6 (2016): 31779.
14. Getz AM., et al. “Tumor suppressor menin is required for subunit-specific nAChR α5 transcription and nAChR-dependent presynaptic facilitation in cultured mouse hippocampal neurons”. Scientific Reports1 (2017).
15. Batool S., et al. “Spatiotemporal Patterns of Menin Localization in Developing Murine Brain: Co-Expression with the Elements of Cholinergic Synaptic Machinery”. Cells5 (2021): 1215.
16. Zhuang K., et al. “Neuron-Specific Menin Deletion Leads to Synaptic Dysfunction and Cognitive Impairment by Modulating p35 Expression”. Cell Reports3 (2018): 701-712.
17. Leng L., et al. “Menin Deficiency Leads to Depressive-like Behaviors in Mice by Modulating Astrocyte-Mediated Neuroinflammation”. Neuron3 (2018): 551-563.e7.
18. Kesteren RE., et al. “Synapse formation between central neurons requires postsynaptic expression of the MEN1 tumor suppressor gene”. The Journal of Neuroscience 16 (2001): RC161.
19. Lahey T., et al. “The Drosophila tumor suppressor gene dlg is required for normal synaptic bouton structure”. Neuron4 (1994): 823-835.
20. Soltani MH., et al. “Microtubule-associated protein 2, a marker of neuronal differentiation, induces mitotic defects, inhibits growth of melanoma cells, and predicts metastatic potential of cutaneous melanoma”. The American Journal of Pathology6 (2005): 1841-1850.
21. Eastwood SL., et al. “Synaptophysin gene expression in human brain: a quantitative in situ hybridization and immunocytochemical study”. Neuroscience4 (1994): 881-892.
22. Yoo KS., et al. “Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions”. Molecular Brain 97 (2019).
23. Placzek AN., et al. “Age dependent nicotinic influences over dopamine neuron synaptic plasticity”. Biochemical Pharmacology7 (2009): 686-692.
24. Reas ET. “Amyloid and Tau Pathology in Normal Cognitive Aging”. The Journal of Neuroscience: the Official Journal of the Society for Neuroscience32 (2017): 7561-7563.
25. Allen SJ., et al. “The neurotrophins and their role in Alzheimer's disease”. Current Neuropharmacology4 (2011): 559-573.
26. Morgan DG. “Considerations in the treatment of neurological disorders with trophic factors”. Neurobiology of Aging5 (1989): 547-549.
27. Hefti F and Weiner WJ. “Nerve growth factor and Alzheimer's disease”. Annals of Neurology3 (1986): 275-281.
28. Berendse HW., et al. “Magnetoencephalographic analysis of cortical activity in Alzheimer's disease: a pilot study”. Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology4 (2000): 604-612.
29. Goutagny R and Krantic S. “Hippocampal oscillatory activity in Alzheimer's disease: toward the identification of early biomarkers?” Aging and Disease3 (2013): 134-140.
30. Marceglia S., et al. “Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease”. Frontiers in Neuroscience 10 (2016): 134.
31. Canchi S., et al. “Integrating Gene and Protein Expression Reveals Perturbed Functional Networks in Alzheimer's Disease”. Cell Reports4 (2019): 1103-1116.e4.
32. Li L., et al. “Egr3, a synaptic activity regulated transcription factor that is essential for learning and memory”. Molecular and Cellular Neurosciences1 (2007): 76-88.
33. Savioz A., et al. “A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease”. Ageing Research Reviews 18 (2014): 86-94.
34. Almeida CG., et al. “Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses”. Neurobiology of Disease2 (2005): 187-198.
35. Perrone-Bizzozero NI., et al. “Levels of the growth-associated protein GAP-43 are selectively increased in association cortices in schizophrenia”. Proceedings of the National Academy of Sciences of the United States of America24 (1996): 14182-14187.
36. Glantz LA and Lewis DA. “Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity”. Archives of General Psychiatry10 (1997): 943-952.
37. Honer WG., et al. “Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness”. Neuroscience4 (1999): 1247-1255.
38. Glantz LA., et al. “Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood”. Neuroscience3 (2007): 582-591.
39. Yuki D., et al. “DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer's disease”. Scientific Reports 4 (2014): 7130.
40. Van Minnen J., et al. “De novo protein synthesis in isolated axons of identified neurons”. Neuroscience1 (1997): 1-7.
41. Van Minnen J and Syed NI. “Local protein synthesis in invertebrate axons: from dogma to dilemma”. Results and Problems in Cell Differentiation 34 (2001): 175-196.
42. Gudi V., et al. “Synaptophysin Is a Reliable Marker for Axonal Damage”. Journal of Neuropathology and Experimental Neurology2 (2017): 109-125.
43. Wevers A., et al. “Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein”. The European Journal of Neuroscience7 (1999): 2551-2565.