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Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPα)

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Abstract

Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aβ) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer’s disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer’s disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer’s disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.

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Abbreviations

APP:

Amyloid precursor protein

sAPPα:

Secreted amyloid precursor protein alpha

ADAM 10:

A disintegrin and metalloproteinase domain-containing protein 10

BACE1:

Beta-secretase enzyme 1

CCI:

Controlled cortical impact

IDE:

Insulin degrading enzyme

NSC:

Neural stem cell

NMDA:

N-Methyl-d-aspartate

SGZ:

Subgranular zone

SVZ:

Sub-ventricular zone

TBI:

Traumatic brain injury

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Acknowledgements

The research is currently supported by grants to GWG from St. Boniface Hospital Research Foundation (SBHF-7069), Winnipeg, Canada. We would like to thank Dr. JA Bhat (University of Rochester, NY) for his constant advice throughout manuscript preparation.

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  1. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada

    Nawab John Dar & Gordon W. Glazner

  2. St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB, R2H 2A6, Canada

    Nawab John Dar & Gordon W. Glazner

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Dar, N.J., Glazner, G.W. Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPα). Cell. Mol. Life Sci. 77, 2315–2330 (2020). https://doi.org/10.1007/s00018-019-03404-x

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