JOURNAL ARTICLE

Precursor-Independent Overproduction of Beta-Amyloid in AD: Mitochondrial Dysfunction as Possible Initiator of Asymmetric RNA-Dependent βAPP mRNA Amplification. An Engine that Drives Alzheimer's Disease

Vladimir Volloch, Bjorn R Olsen, Sophia Rits
Annals of integrative molecular medicine 2019, 1 (1): 61-74
31858090
The present study defines RNA-dependent amplification of βAPP mRNA as a molecular basis of beta-amyloid overproduction in Alzheimer's disease. In this process, βAPP mRNA serves as a template for RNA-dependent RNA polymerase, RdRp complex. The resulting antisense RNA self-primes its extension utilizing two complementary elements: 3'-terminal and internal, located within an antisense segment corresponding to the coding portion of βAPP mRNA. The extension produces 3'-terminal fragment of βAPP mRNA, a part of a hairpin-structured antisense/sense RNA molecule. Cleavage at the 3' end of the hairpin loop produces RNA end product encoding a C-terminal fragment of βAPP. Since each conventional βAPP mRNA can be used repeatedly as a template, the process constitutes an asymmetric mRNA amplification. The 5'-most translation initiation codon of the amplified mRNA is the AUG preceding immediately and in-frame the Aβ-coding segment. Translation from this codon overproduces Aβ independently of βAPP. Such process can occur in humans but not in mice and other animals where segments of βAPP antisense RNA required for self-priming have little, if any, complementarity. This explains why Alzheimer's disease occurs exclusively in humans and implies that βAPP mRNA amplification is requisite in AD. In AD, therefore, there are two pathways of beta-amyloid production: βAPP proteolytic pathway and βAPP mRNA amplification pathway independent of βAPP and insensitive to beta-secretase inhibition. This implies that in healthy humans, where only the proteolytic pathway is in operation, Aβ production should be suppressed by the BACE inhibition, and indeed it is. However, since βAPP-independent pathway operating in AD is by far the predominant one, BACE inhibition has no effect in Alzheimer's disease. It appears that, physiologically, the extent of beta-amyloid overproduction sufficient to trigger amyloid cascade culminating in AD requires asymmetric RNA-dependent amplification of βAPP mRNA and cannot be reached without it. In turn, the occurrence of mRNA amplification process depends on the activation of inducible components of RdRp complex by certain stresses, for example the ER stress in case of amplification of mRNA encoding extracellular matrix proteins. In case of Alzheimer's disease, such an induction appears to be triggered by stresses associated with mitochondrial dysfunction, a phenomenon closely linked to AD. The cause-and-effect relationships between mitochondrial dysfunction and AD appear to be very different in familial, FAD, and sporadic, SAD cases. In FAD, increased levels or more toxic species of Aβ resulting from the abnormal proteolysis of βAPP trigger mitochondrial dysfunction, activate mRNA amplification and increase the production of Aβ, reinforcing the cycle. Thus in FAD, mitochondrial dysfunction is an intrinsic component of the amyloid cascade. The reverse sequence is true in SAD where aging-related mitochondrial dysfunction activates amplification of βAPP mRNA and enhances the production of Aβ. This causes further mitochondrial dysfunction, the cycle repeats and degeneration increases. Thus in SAD, the initial mitochondrial dysfunction arises prior to the disease, independently of and upstream from the increased Aβ production, i.e. in SAD, mitochondrial pathology hierarchically supersedes Aβ pathology. This is the primary reason for the formulation of the Mitochondrial Cascade Hypothesis. But even in terms of the MCH, the core of the disease is the amyloid cascade as defined in the amyloid cascade hypothesis, ACH. The role of mitochondrial dysfunction in relation to this core is causative in SAD and auxiliary in FAD. In FAD, the initial increase in the production of Aβ is mutations-based and occurs relatively early in life, whereas in SAD it is coerced by an aging-contingent component, but both lead to mechanistically identical self-perpetuating mutual Aβ/mitochondrial dysfunction feedback cycles, an engine that drives, via RNA-dependent βAPP mRNA amplification, overproduction of beta-amyloid and, consequently, AD; hence drastic difference in the age of onset, yet profound pathological and symptomatic similarity in the progression, of familial and sporadic forms of Alzheimer's disease. Interestingly, the recent findings that mitochondrial microprotein PIGBOS interacts with the ER in mitigating the unfolded protein response indicate a possible connection between mitochondrial dysfunction and ER stress, implicated in activation of RNA-dependent mRNA amplification pathway. The possible involvement of mitochondrial dysfunction in βAPP mRNA amplification makes it a promising therapeutic target. Recent successes in mitigating, and even reversing, Aβ-induced metabolic defects with anti-diabetes drug metformin are encouraging in this respect.

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