The DOI matches its Crossref record; 178 of the 181 references it cites were found in a registry or an index.
The keystone of Alzheimer pathogenesis might be sought in Aβ physiology
Open accessAbstract
For several years Amyloid-beta peptide (Aβ) has been considered the main pathogenetic factor of Alzheimer's disease (AD). According to the so called Amyloid Cascade Hypothesis the increase of Aβ triggers a series of events leading to synaptic dysfunction and memory loss as well as to the structural brain damage in the later stage of the disease. However, several evidences suggest that this hypothesis is not sufficient to explain AD pathogenesis, especially considering that most of the clinical trials aimed to decrease Aβ levels have been unsuccessful. Moreover, Aβ is physiologically produced in the healthy brain during neuronal activity and it is needed for synaptic plasticity and memory. Here we propose a model interpreting AD pathogenesis as an alteration of the negative feedback loop between Aβ and its physiological receptors, focusing on alpha7 nicotinic acetylcholine receptors (α7-nAchRs). According to this vision, when Aβ cannot exert its physiological function a negative feedback mechanism would induce a compensatory increase of its production leading to an abnormal accumulation that reduces α7-nAchR function, leading to synaptic dysfunction and memory loss. In this perspective, the indiscriminate Aβ removal might worsen neuronal homeostasis, causing a further impoverishment of learning and memory. Even if further studies are needed to better understand and validate these mechanisms, we believe that to deepen the role of Aβ in physiological conditions might represent the keystone to elucidate important aspects of AD pathogenesis.
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“Soluble Aβ exerts a physiological function, modulating synaptic function and facilitating neuronal growth; furthermore, Aβ protects the brain from infections, repairs leaks in the blood–brain barrier, and promotes recovery from injury [57, 58].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [57]
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“Under healthy conditions, soluble monomeric Aβ contributes to synaptic regulation, neuronal signaling, and neuroprotection through modulation of calcium homeostasis, metal ion binding, and antimicrobial defense [41–43].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [43]
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Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 2×
“, 1999) have been found in soluble fractions and in extracts of plaques in AD brains and CSF (Podlisny et al., 1995; Roher et al., 1996; Funato et al., 1998; Enya et al., 1999; McLean et al., 1999; Kawarabayashi et al., 2004; Lesne et al., 2006); (ii) administration of Ab oligomers (synthetic, derived from AD brains o…”
RetractedAmyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
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Alzheimer's Disease Is a Synaptic Failure
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Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins
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Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Arriagada, P. V., Growdon, J. H., Hedley-Whyte, E. T., & Hyman, B. T. (1992) · Neurology · doi:10.1212/wnl.42.3.631 · Cited by 2,668
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538
Cited by
Sorted by citations
Amyloid Beta: Structure, Biology and Structure-Based Therapeutic Development
Chen, G.-F., Xu, T.-H., Yan, Y., Zhou, Y.-R., Jiang, Y., Melcher, K., & Xu, H. E. (2017) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.28 · Cited by 1,965
A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease
Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0116-6 · Cited by 965
Clinical trials of new drugs for Alzheimer disease
Huang, L.-K., Chao, S.-P., & Hu, C.-J. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-019-0609-7 · Cited by 702
“Soluble Aβ exerts a physiological function, modulating synaptic function and facilitating neuronal growth; furthermore, Aβ protects the brain from infections, repairs leaks in the blood–brain barrier, and promotes recovery from injury [57, 58].”
BackgroundThe Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease
Brothers, H. M., Gosztyla, M. L., & Robinson, S. R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00118 · Cited by 314
Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade
Gulisano, W., Maugeri, D., Baltrons, M. A., Fà, M., Amato, A., Palmeri, A., D’Adamio, L., Grassi, C., Devanand, D. P., Honig, L. S., et al. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179935 · Cited by 313
Self-citation
Metadata
- Authors
- Puzzo, D., Gulisano, W., Arancio, O., & Palmeri, A.
- Affiliations
- University of Catania (IT)
- Columbia University (US)
- Corresponding author
- Puzzo, D.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 307
- Pages
- 26-36
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC4591241
- OpenAlex
- W1149434589
- Cited by
- 116
- References
- 181
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 8 · 2022: 7 · 2021: 14 · 2020: 7 · 2019: 15 · 2018: 11 · 2017: 17 · 2016: 23 · 2015: 2
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer’s Association (NIRG-07-59597, IIRG-09-134220)
- National Institutes of Health (NS049442, AG034248)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease pathogenesis, amyloid-beta, amyloid hypothesis, alpha7 nicotinic acetylcholine receptor, negative feedback loop, synaptic plasticity, memory loss, synaptic dysfunction
- MeSH terms
- Alzheimer Disease, Animals, Humans, Signal Transduction, Amyloid beta-Peptides, Amyloid beta-Protein Precursor
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