The pathological trajectory of Alzheimer’s Disease (AD) has often been charted through the degradation of memory and cognitive faculties, predominantly attributed to amyloid-β plaques and tau tangles disrupting neural pathways. However, a burgeoning area of research is challenging the singularity of this paradigm, focusing on an alternative but complimentary line of inquiry: why do some individuals show no symptoms of cognitive decline despite presenting histological markers typical of Alzheimer’s? This question has taken on newfound significance in the wake of a recent groundbreaking study published in the journal Cell (Mathys et al., 2023).
Researchers Mathys, Tsai, and Kellis—affiliated with prestigious institutions like the University of Pittsburgh and the Massachusetts Institute of Technology—conducted a nuanced exploration of neuronal types in relation to dementia and Alzheimer’s. Leveraging advanced single-cell sequencing techniques, they examined 427 post-mortem brain samples to create a comprehensive cellular atlas of the human prefrontal cortex. Remarkably, they identified two specific neuronal types marked by distinct genetic indicators—reelin and somatostatin—as being inversely correlated with cognitive impairment. These findings shift the spotlight onto the neuroprotective qualities of specific inhibitory neurons and indicate the potential for a seismic shift in our therapeutic approach to Alzheimer’s Disease.
Importantly, the study adds a layer of complexity to the dominant model of AD pathogenesis that implicates amyloid-β plaques. Despite the presence of these plaques, a subset of individuals displayed high numbers of reelin- and somatostatin-expressing neurons and no cognitive impairment, suggesting an as-yet-undetermined resilience mechanism. These findings align with another recent study that reported a reelin gene mutation in a subject with high levels of amyloid but no signs of AD (Lopera et al., 2023).
As neurologists, gerontologists, and neuroscientists grapple with the multi-faceted enigma that is Alzheimer’s, this avenue of research provides a promising new frontier. Could the preservation or even augmentation of these specific inhibitory neurons offer a viable strategy for mitigating cognitive decline? This article delves into the implications of these seminal findings, their potential to reshape our understanding of Alzheimer’s Disease, and the prospective pathways for novel treatments focused on neuronal resilience rather than amyloid-β targeting.
Reelin and Somatostatin: Molecules of Neurological Resilience
Reelin: Beyond Neural Migration and Plasticity
Traditionally associated with neuronal migration and plasticity, reelin is a large extracellular matrix glycoprotein that plays a critical role in the formation of laminated brain structures during development (Tissir & Goffinet, 2003). However, the recent research by Mathys et al. (2023) adds an unexpected and fascinating dimension to our understanding of reelin: its role as a genetic marker for neuronal types linked to resilience against Alzheimer’s Disease. Previously, research has also indicated that reelin is associated with certain psychiatric disorders like schizophrenia (Impagnatiello et al., 1998). This dual role—implicated in both developmental abnormalities and potential neuroprotection—marks reelin as a protein of interest in neuropsychiatric research.
Mathys et al. (2023) found neurons with active genes coding for reelin in samples from individuals who had high levels of amyloid plaques but showed no cognitive impairment. This lends credence to the hypothesis that reelin may be part of a neuroprotective mechanism that could counterbalance the detrimental effects of amyloid-β accumulation. While the mechanistic details are not yet fully elucidated, the identification of reelin-expressing neurons as a potential buffer against cognitive decline merits further exploration.
Somatostatin: A Hormone with Multiple Facets
Somatostatin, a cyclic peptide hormone, is widely known for its regulatory effects on endocrine system functions, including the inhibition of growth hormone and insulin (Patel, 1999). However, in the central nervous system, somatostatin also serves as a neurotransmitter and has been found in inhibitory interneurons. In Alzheimer’s research, somatostatin’s presence has been generally overlooked in favor of more traditional markers and proteins. Mathys et al. (2023) challenge this oversight by identifying somatostatin-expressing neurons as another neuronal type inversely correlated with cognitive decline.
Neurons with active genes coding for somatostatin were similarly abundant in samples from individuals showing no signs of cognitive decline, despite having histological markers traditionally associated with Alzheimer’s. As with reelin, the presence of somatostatin-expressing neurons suggests a potential neuroprotective role, one which is likely to alter the direction of future research significantly. While somatostatin has been implicated in various physiological processes, its potential role in mitigating or preventing Alzheimer’s symptoms has not been comprehensively studied until now.
Toward a New Neurobiological Paradigm
The identification of reelin and somatostatin as markers for specific neuronal types linked to Alzheimer’s resilience prompts a reevaluation of our neurobiological paradigms. These molecules may offer both diagnostic markers for assessing Alzheimer’s risk and therapeutic targets for developing treatments that focus on neural resilience as opposed to merely countering amyloid-β accumulation.
In summary, the emergent roles of reelin and somatostatin as agents of neuroprotection against Alzheimer’s Disease provide compelling avenues for future research. The task ahead is multi-faceted, requiring a deeper mechanistic understanding of how these neuronal types confer resilience, the development of diagnostic tools based on these markers, and the translation of these insights into clinically effective treatments.
References
- Tissir, F., & Goffinet, A. M. (2003). Reelin and brain development. Nature reviews. Neuroscience, 4(6), 496–505.
- Impagnatiello, F., Guidotti, A. R., Pesold, C., Dwivedi, Y., Caruncho, H., Pisu, M. G., … & Costa, E. (1998). A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proceedings of the National Academy of Sciences, 95(26), 15718-15723.
- Patel, Y. C. (1999). Somatostatin and its receptor family. Frontiers in neuroendocrinology, 20(3), 157-198.
- Mathys, H. et al. Cell https://doi.org/10.1016/j.cell.2023.08.039 (2023).
- Lopera, F. et al. Nature Med. 29, 1243–1252 (2023).
Amino Acid Composition of Reelin and Somatostatin: Nutritional Considerations and Plant Sources
The Amino Acid Profiles of Reelin and Somatostatin
Reelin
Reelin is a large glycoprotein comprised of approximately 3460 amino acids and plays crucial roles in brain development and neural plasticity (Tissir & Goffinet, 2003). While the full amino acid sequence is beyond the scope of this discussion, it is essential to understand that it contains multiple domains rich in the basic amino acids arginine and lysine, as well as serine residues that undergo phosphorylation. These regions of the protein are essential for its biological activity and interactions with cellular receptors like ApoER2 and VLDLR (D’Arcangelo et al., 1999).
Somatostatin
In contrast, somatostatin is a much smaller peptide hormone, commonly existing in two bioactive forms: one composed of 14 amino acids and another with 28 amino acids. The amino acid sequence of the 14-amino acid form is AGCKNFFWKTFTSC, representing a range of amino acids such as alanine (A), glycine (G), cysteine (C), and so on. The cyclic nature of the hormone, formed through a disulfide bond between the cysteine residues, is crucial for its bioactivity (Patel, 1999).
Nutritional Implications: Amino Acids in Plants
Amino acids, the building blocks of proteins, are available from a variety of dietary sources, including plants. While no plant source directly produces the specialized proteins reelin and somatostatin, certain plants are rich in the essential amino acids that contribute to the biosynthesis of these complex molecules in animals.
Lysine and Arginine
Lysine-rich plants include legumes like lentils and chickpeas, while arginine is abundant in seeds like pumpkin and sunflower seeds (Young & Pellett, 1994).
Alanine and Glycine
For amino acids like alanine and glycine, which are part of somatostatin’s structure, soybeans and spirulina offer a rich source (Wu, 2010).
Cysteine
Cysteine, another crucial amino acid for somatostatin, is found in high levels in garlic and onions (Bender, 2014).
Serine
Serine, essential for reelin’s phosphorylation, can be found in abundance in soybeans and sunflower seeds (Rutherfurd et al., 2015).
Conclusion: Toward a Nutraceutical Approach?
While it is a significant leap to suggest that dietary intake of these amino acids could influence the levels or functioning of reelin and somatostatin in the brain, understanding the amino acid composition of these neuroprotective molecules opens avenues for further research. Could a targeted diet rich in these amino acids influence the brain’s resilience to Alzheimer’s Disease? Future research in this interdisciplinary space between nutrition and neurobiology will be critical for answering such questions.
References
- Tissir, F., & Goffinet, A. M. (2003). Reelin and brain development. Nature reviews. Neuroscience, 4(6), 496–505.
- D’Arcangelo, G., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K., & Curran, T. (1997). Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody. The Journal of Neuroscience, 17(1), 23-31.
- Patel, Y. C. (1999). Somatostatin and its receptor family. Frontiers in neuroendocrinology, 20(3), 157-198.
- Young, V. R., & Pellett, P. L. (1994). Plant proteins in relation to human protein and amino acid nutrition. The American Journal of Clinical Nutrition, 59(5), 1203S-1212S.
- Wu, G. (2010). Functional amino acids in nutrition and health. Amino acids, 37(1), 1-17.
- Bender, D. A. (2014). Amino Acid Metabolism. John Wiley & Sons.
- Rutherfurd, S. M., Fanning, A. C., Miller, B. J., & Moughan, P. J. (2015). Protein digestibility-corrected amino acid scores and digestible indispensable amino acid scores differentially describe protein quality in growing male rats. The Journal of Nutrition, 145(2), 372-379.