Therapeutic Options for Alzheimer's Disease and Aging-Associated Cognitive Decline: State of the Art in the ACH2.0 Paradigm.

In the Amyloid Cascade Hypothesis (ACH2.0) paradigm, Alzheimer's disease (AD) is defined as a disorder triggered by a sustained neuronal integrated stress response (ISR) and driven by the C99 fragment of amyloid-beta protein precursor (AβPP) generated in the autonomous AβPP-independent pathway. This implies that AD can be initiated by any stressor capable of activating one or more of the four eIF2α kinases and accumulated intraneuronally to sufficient levels. In most instances of AD, such a stressor is intraneuronal Aβ (iAβ) accumulated to a PKR- and/or HRI-activating concentration and designated, in terms of the ACH2.0, as a "conventional stressor". The ensuing disease is referred to, accordingly, as "conventional AD". Any stressor other than iAβ, which is capable of activating one or more eIF2α kinases in neuronal cells, is designated as an "unconventional stressor". At a sufficient concentration, it triggers elicitation of the neuronal ISR and initiates the disease, referred to in terms of the ACH2.0 as "unconventional AD", at levels of iAβ below those required for activation of PKR and/or HRI. In both forms of AD, the neuronal ISR activates production of components essential for, and, consequently, enables operation of, the RNA-dependent mRNA amplification pathway. Human AβPP mRNA is eligible for this process, and its asymmetric amplification yields 5'-truncated mRNA molecules that are translated into C99 at rates that are orders of magnitude greater than those seen in AβPP proteolysis. The resulting C99 drives AD pathology; it also propagates the ISR state and perpetuates both its own production and the progression of the disease. Thus, the neuronal ISR-enabled amplification of AβPP mRNA constitutes the active core of AD. It follows that the essence of any effective therapy for AD, in both conventional and unconventional forms, is to either prevent activation or suppress the operation of the AβPP mRNA amplification process. The present perspective considers therapeutic options capable of accomplishing these objectives. They include inhibition of the neuronal ISR, targeted degradation of iAβ and C99, anti-antisense oligonucleotides (AASO) for AβPP RNA, and the restructuring of the 5' terminus of AβPP mRNA. Collectively, these therapeutic approaches constitute the state of the art in the ACH2.0 paradigm; if successful, they would render both AD and aging-associated cognitive decline (AACD) obsolete. This study also describes transgenic animal and human neuronal cell-based models of both conventional and unconventional forms of AD that are suitable for testing the proposed therapeutic strategies.