The Carnitine Palmitoyl-Transferase 2 Cascade Hypothesis for Alzheimer’s Disease

Article type: Research Article

Authors: Keizer, Hiskias G.^{a; b; *} | Brands, Ruud^{a; b; c} | Oosting, Ronald S.^{a; b} | Seinen, Willem^{a; b; c}

Affiliations: [a] Alloksys Biotechnology, Wageningen, The Netherlands | [b] AMRIF Biotechnology, Wageningen, The Netherlands | [c] Institute for Risk Assessment Sciences (IRAS), Utrecht, The Netherlands

Correspondence: [*] Correspondence to: Hiskias G. Keizer, PhD, Alloksys Biotechnology, Agrobusiness Park 10, 6708 PW, Wageningen, The Netherlands. Tel.: +31 640339818; E-mail: [email protected]; ORCID: 0000-0002-9988-6387.

Abstract: Despite decades of intense research, the precise etiology of Alzheimer’s disease (AD) remains unclear. In this hypothesis, we present a new perspective on this matter by identifying carnitine palmitoyl transferase-2 (CPT2) as a central target in AD. CPT2 is an enzyme situated within the inner mitochondrial membrane, playing a crucial role in beta-oxidation of fatty acids. It exhibits high sensitivity to hydrogen peroxide. This sensitivity holds relevance for the etiology of AD, as all major risk factors for the disease share a commonality in producing an excess of hydrogen peroxide right at this very mitochondrial membrane. We will explain the high sensitivity of CPT2 to hydrogen peroxide and elucidate how the resulting inhibition of CPT2 can lead to the characteristic phenotype of AD, thus clarifying its central role in the disease’s etiology. This insight holds promise for the development of therapies for AD which can be implemented immediately.

Keywords: Alzheimer’s disease, AMP-kinase pathway dependent integrated stress response, carnitine palmitoyl transferase 2, CPT2, hydrogen peroxide, hypoxia, longevity, radical oxygen species

DOI: 10.3233/JAD-230991

Journal: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 553-558, 2024