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What is the physiological function of amyloid-beta protein?

  • J. E. MorleyEmail author
  • S. A. Farr
  • A. D. Nguyen
  • F. Xu
Editorial
  • 42 Downloads

Key words

Amyloid-beta protein physiological function central nervous system 

Most of the studies of amyloid-beta (Aβ) have concentrated on the pathological effects of high levels of the protein in causing cognitive impairment and Alzheimer’s disease (1). There is some evidence that the Amyloid Precursor Protein (APP) has a physiological trophic function on the central nervous system (2). APP knockout mice are viable but have smaller brains and alterations in neurogenesis (3). APP plays a role in the nervous system, possibly through promotion of neurite outgrowth and also long-term potentiation (LTP) by modulation of calcium release (4, 5).

In neuronal cultures, inhibition of Aβ production by blocking beta-secretase leads to neuronal cell death, and this can be prevented by providing physiological doses of Aβ (in the picomolar range) (6). Aβ at physiological levels reduces the excitatory activity of potassium channels and reduces neuronal apoptosis (7). Soucek et al (8) have suggested that a physiological effect of Aβ during aging is neuroprotection, secondary to its ability to induce hypoxia inducible factor-1α.

Other suggested physiological effects of Aβ include antimicrobial activity, blocking leaks in the blood-brainbarrier, enhancing recovery from posttraumatic brain injury and possibly suppressing cancer through inhibition of oncogenic viruses (9).

Aβ at picomolar concentrations enhances synaptic plasticity and learning and memory in animals by promoting LTP in the hippocampus. Its action involves increasing the release of the neurotransmitter acetylcholine and activation of nicotinic acetylcholine receptors (10-12). However, it is important to note that prolonged exposure is associated with tolerance leading to reduced effects of Aβ.

Ours and many other studies on neurotransmitter roles in memory have demonstrated that while low (physiological) doses enhance memory, high (pathological) doses inhibit memory (13-15). This phenomenon is known as hormesis (16). Specifically, our group had shown that high doses of Aβ inhibited memory in mice (17), while low dose (picomolar) quantities of Aβ enhanced memory in mice (10). This has been consistent with results demonstrated by others (11, 12). We further showed that the converse was true, as both antibodies to Aβ and antisense to APP mRNA resulted in impaired memory in young mice (17).

The physiological role of Aβ explains why when drugs that reduce Aβ are used to treat Alzheimer’s disease they fail (18-20). This is due to these drugs eventually reducing the Aβ to values where they interfere with the physiological activities of Aβ.

In an attempt to reduce Aβ to normal levels but be able to modulate the treatment to prevent lowering levels below normal, we have developed a series of antisense to APP (21, 22). These antisenses reduce Aβ to the normal range, improve memory, decrease oxidative damage and improve bloodbrain- barrier function in mouse models of Alzheimer’s disease (23-27). These antisenses can be administered intranasally. We believe that antisenses such as these may well have a therapeutic role in the management of Alzheimer’s disease in humans.

In conclusion, this editorial argues that the physiological role of Aβ is to improve memory (Figure 1), and it is only when Aβ levels are markedly increased that they result in dementia as predicted by the “Amyloid Hypothesis.”
Figure 1

The physiological role of amyloid-beta peptide

References

  1. 1.
    Morley JE, Farr SA, Nguyen AD. Alzheimer disease. Clin Geriatr Med 2018;34:591–601.CrossRefGoogle Scholar
  2. 2.
    Dawkins E, Small DH. Insights into the physiological function of the ß-amyloid precursor protein: Beyond Alzheimer’s disease. J Neurochemistry 2014;129:756–769.CrossRefGoogle Scholar
  3. 3.
    Wang S, Bolos M, Clark R, et al. Amyloid ß precursor protein regulates neuron survival and maturation in the adult mouse brain. Mol Cell Neurosci 2016;77:21–33.CrossRefGoogle Scholar
  4. 4.
    Masliah E, Mallory M, Ge N, Saitoh T. Amyloid precursor protein is localized in growing neurites of neonatal rat brain. Brain Res 1992;593:323–328.CrossRefGoogle Scholar
  5. 5.
    Kim HS, Park CH, Cha SH, et al. Carboxyl-terminal fragment of Alzheimer’s APP destabilizes calcium homeostasis and renders neuronal cells vulnerable to excitotoxicity. FASEB J 2000;14:1508–1517.Google Scholar
  6. 6.
    Pearson HA, Peers C. Physiological roles for amyloid ß peptides. J Physiol 2006;575(1):5–10.CrossRefGoogle Scholar
  7. 7.
    Yu HB, Li ZB, Zhang HX, Wang XL. Role of potassium channels Abeta (1-40)-activated apoptotic pathway in cultured cortical neurons. J Neurosci Res 2006;84:1475–1484.CrossRefGoogle Scholar
  8. 8.
    Soucek T, Cumming R, Dargusch R, et al. The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron 2003;39:43–56.CrossRefGoogle Scholar
  9. 9.
    Brothers HM, Gosztyla ML, Robinson SR. The physiological roles of amyloid-ß peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci 2018;10:118.CrossRefGoogle Scholar
  10. 10.
    Morley JE, Farr SA, Banks WA, et al. A physiological role for amyloid-beta protein: Enhancement of learning and memory. J Alzheimers Dis 2010;19:441–449.CrossRefGoogle Scholar
  11. 11.
    Puzzo D, Privitera L, Fa’ M, et al. Endogenous amyloid-ß is necessary for hippocampal synaptic plasticity and memory. Ann Neurol 2011;69:819–830.CrossRefGoogle Scholar
  12. 12.
    Puzzo D, Privitera L, Leznik E, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 2008;28:14537–14545.CrossRefGoogle Scholar
  13. 13.
    Flood JF, Roberts E, Sherman MA, et al. Topography of a binding site for small amnestic peptides deduced from structure-activity studies: Relation to amnestic effect of amyloid beta protein. Proc Natl Acad Sci U S A 1994;91:380–384.CrossRefGoogle Scholar
  14. 14.
    Flood JF, Morley JE, Roberts E. Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease. Proc Natl Acad Sci U S A 1991;88:3363–3366.CrossRefGoogle Scholar
  15. 15.
    Flood JF, Morley JE, Roberts E. An amyloid beta-protein fragment, a beta[12-28], equipotently impairs post-training memory processing when injected into different limbic system structures. Brain Res 1994;663:271–276.CrossRefGoogle Scholar
  16. 16.
    Morley JE, Farr SA. Hormesis and amyloid-ß protein: Physiology or pathology? J Alzheimers Dis 2012;29:487–492.CrossRefGoogle Scholar
  17. 17.
    Morley JE, Farr SA. The role of amyloid-beta in the regulation of memory. Biochem Pharmacol 2014;88:479–485.CrossRefGoogle Scholar
  18. 18.
    Lista S, Dubois B, Hampel H. Paths to Alzheimer’s disease prevention: From modifiable risk factors to biomarker enrichment strategies. J Nutr Health Aging 2015;19;154–163.CrossRefGoogle Scholar
  19. 19.
    Morley JE, Farr SA. Alzheimer mythology: A time to think out of the box. J Am Med Dir Assoc 2016;17:769–774.CrossRefGoogle Scholar
  20. 20.
    Morley JE, Morris JC, Berg-Weger M, et al. Brain health: The importance of recognizing cognitive impairment; An IAGG consensus conference. J Am Med Dir Assoc 2015;16:731–739.CrossRefGoogle Scholar
  21. 21.
    Poon HF, Farr SA, Banks WA, et al. Proteomic identification of less oxidized brain proteins in aged senescence-accelerated mice following administration of antisense oligonucleotide directed at the Abeta region of amyloid precursor protein. Poon HF, Farr SA, Banks WA, et al. Brain Res Mol Brain Res 2005;138:8–16.CrossRefGoogle Scholar
  22. 22.
    Poon HF, Joshi G, Sultana R, et al. Antisense directed at the Abeta region of APP decreases brain oxidative markers in aged senescence accelerated mice. Brain Res 2004;1018:86–96.CrossRefGoogle Scholar
  23. 23.
    Morley JE, Farr SA, Kumar VB, Armbrecht HJ. The SAMP8 mouse: A model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 2012;18:1123–1130.CrossRefGoogle Scholar
  24. 24.
    Banks WA, Farr SA, Butt W, et al. Delivery across the blood-brain barrier of antisense directed against amyloid beta: Reversal of learning and memory deficits in mice overexpressing amyloid precursor protein. J Pharmacol Exp Ther 2001;297:1113–1121.Google Scholar
  25. 25.
    Kumar VB, Farr SA, Flood JF, et al. Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice. Peptides 2000;21:1769–1775.CrossRefGoogle Scholar
  26. 26.
    Morley JE, Armbrecht HJ, Farr SA, Kumar UB. The senescence accelerated mouse (SAMP8) as a model for oxidative stress and alzheimer’s disease. Biochim Biophys Acta 2012;1822:650–656.CrossRefGoogle Scholar
  27. 27.
    Banks WA, Kumar VB, Farr SA, et al. Impairments in brain-to-blood transport of amyloid-ß and reabsorption of cerebrospinal fluid in an animal model of Alzheimer’s disease are reversed by antisense directed against amyloid-ß protein precursor. J Alzheimers Dis 2011;23:599–605.CrossRefGoogle Scholar

Copyright information

© Serdi and Springer-Verlag France SAS, part of Springer Nature 2019

Authors and Affiliations

  • J. E. Morley
    • 1
    • 4
    Email author
  • S. A. Farr
    • 1
    • 2
  • A. D. Nguyen
    • 1
  • F. Xu
    • 3
  1. 1.Division of Geriatric MedicineSaint Louis University School of MedicineSt. LouisUSA
  2. 2.Research & Development Service, VA Medical CenterSt. LouisUSA
  3. 3.Department of BiologySaint Louis UniversitySt. LouisUSA
  4. 4.Division of Geriatric MedicineSaint Louis University School of MedicineSt. LouisUSA

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