Sturchio A, Dwivedi AK, Young CB, Malm T, Marsili L, Sharma JS, Mahajan A, Hill EJ, Andaloussi SE, Poston KL, Manfredsson FP, Schneider LS, Ezzat K, Espay AJ. High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis. EClinicalMedicine. 2021 Aug;38:100988. Epub 2021 Jun 28 PubMed.

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  1. I read with great interest the paper by Espay’s lab, which favors the hypothesis of a loss of function of the Aβ protein in the onset of AD neurodegeneration. My laboratory has been studying the physiological functions associated with soluble Aβ monomers for over a decade (Giuffrida et al., 2009; Giuffrida et al., 2015; Santangelo et al., 2021) and, therefore, this paper is more than welcome for us.

    However, I would be cautious in stating that AD is a proteinopenia rather than a proteinopathy, as the two can co-exist. Indeed, the self-association of functional Aβ monomers into soluble toxic oligomers could determine both at the same time. At a certain point, soluble monomers could be depleted by direct interaction with preformed fibrils in secondary nucleation processes. Therefore, we need to understand what the relative contribution of amyloid proteinopenia and proteinopathy is across the neurodegenerative event. Until this is clarified, I agree with being cautious with Aβ-targeting therapeutic strategies. Meanwhile, neuroprotective strategies limiting oligomers toxicity, which are lagging behind, would not hurt.

    References:

    Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, Garozzo D, Nicoletti F, Rizzarelli E, Copani A. Beta-amyloid monomers are neuroprotective. J Neurosci. 2009 Aug 26;29(34):10582-7. PubMed.

    Giuffrida ML, Tomasello MF, Pandini G, Caraci F, Battaglia G, Busceti C, Di Pietro P, Pappalardo G, Attanasio F, Chiechio S, Bagnoli S, Nacmias B, Sorbi S, Vigneri R, Rizzarelli E, Nicoletti F, Copani A. Monomeric ß-amyloid interacts with type-1 insulin-like growth factor receptors to provide energy supply to neurons. Front Cell Neurosci. 2015;9:297. Epub 2015 Aug 7 PubMed.

    Santangelo R, Giuffrida ML, Satriano C, Tomasello MF, Zimbone S, Copani A. β-amyloid monomers drive up neuronal aerobic glycolysis in response to energy stressors. Aging (Albany NY). 2021 Jul 21;13(14):18033-18050. PubMed.

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