On the Inadequacy of the Current Transgenic Animal Models of Alzheimer’s Disease: The Path Forward

For at least two reasons, the current transgenic animal models of Alzheimer’s disease (AD) appear to be patently inadequate. They may be useful in many respects, the AD models; however, they are not. First, they are incapable of developing the full spectrum of the AD pathology. Second, they respond...
Ausführliche Beschreibung

For at least two reasons, the current transgenic animal models of Alzheimer’s disease (AD) appear to be patently inadequate. They may be useful in many respects, the AD models; however, they are not. First, they are incapable of developing the full spectrum of the AD pathology. Second, they respond spectacularly well to drugs that are completely ineffective in the treatment of symptomatic AD. These observations indicate that both the transgenic animal models and the drugs faithfully reflect the theory that guided the design and development of both, the amyloid cascade hypothesis (ACH), and that both are inadequate because their underlying theory is. This conclusion necessitated the formulation of a new, all-encompassing theory of conventional AD—the ACH2.0. The two principal attributes of the ACH2.0 are the following. One, in conventional AD, the agent that causes the disease and drives its pathology is the intraneuronal amyloid-β (<i<i</i<Aβ) produced in two distinctly different pathways. Two, following the commencement of AD, the bulk of Aβ is generated independently of Aβ protein precursor (AβPP) and is retained inside the neuron as <i<i</i<Aβ. Within the framework of the ACH2.0, AβPP-derived <i<i</i<Aβ accumulates physiologically in a lifelong process. It cannot reach levels required to support the progression of AD; it does, however, cause the disease. Indeed, conventional AD occurs if and when the levels of AβPP-derived <i<i</i<Aβ cross the critical threshold, elicit the neuronal integrated stress response (ISR), and trigger the activation of the AβPP-independent <i<i</i<Aβ generation pathway; the disease commences only when this pathway is operational. The <i<i</i<Aβ produced in this pathway reaches levels sufficient to drive the AD pathology; it also propagates its own production and thus sustains the activity of the pathway and perpetuates its operation. The present study analyzes the reason underlying the evident inadequacy of the current transgenic animal models of AD. It concludes that they model, in fact, not Alzheimer’s disease but rather the effects of the neuronal ISR sustained by AβPP-derived <i<i</i<Aβ, that this is due to the lack of the operational AβPP-independent <i<i</i<Aβ production pathway, and that this mechanism must be incorporated into any successful AD model faithfully emulating the disease. The study dissects the plausible molecular mechanisms of the AβPP-independent <i<i</i<Aβ production and the pathways leading to their activation, and introduces the concept of conventional versus unconventional Alzheimer’s disease. It also proposes the path forward, posits the principles of design of productive transgenic animal models of the disease, and describes the molecular details of their construction. Ausführliche Beschreibung

Autor*in:	Vladimir Volloch [verfasserIn] Sophia Rits-Volloch [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Alzheimer’s disease (AD) conventional AD unconventional AD amyloid cascade hypothesis (ACH) ACH-based models of AD ACH-based AD drugs

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 25(2024), 5, p 2981
Übergeordnetes Werk:	volume:25 ; year:2024 ; number:5, p 2981

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms25052981

Katalog-ID:	DOAJ091256259