{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T16:48:23Z","timestamp":1783529303935,"version":"3.55.0"},"reference-count":186,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NIH R21 GM056179"],"award-info":[{"award-number":["NIH R21 GM056179"]}]},{"name":"National Institutes of Health","award":["NIH RO1 AR036819"],"award-info":[{"award-number":["NIH RO1 AR036819"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>For at least two reasons, the current transgenic animal models of Alzheimer\u2019s 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\u2014the 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-\u03b2 (iA\u03b2) produced in two distinctly different pathways. Two, following the commencement of AD, the bulk of A\u03b2 is generated independently of A\u03b2 protein precursor (A\u03b2PP) and is retained inside the neuron as iA\u03b2. Within the framework of the ACH2.0, A\u03b2PP-derived iA\u03b2 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 A\u03b2PP-derived iA\u03b2 cross the critical threshold, elicit the neuronal integrated stress response (ISR), and trigger the activation of the A\u03b2PP-independent iA\u03b2 generation pathway; the disease commences only when this pathway is operational. The iA\u03b2 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\u2019s disease but rather the effects of the neuronal ISR sustained by A\u03b2PP-derived iA\u03b2, that this is due to the lack of the operational A\u03b2PP-independent iA\u03b2 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 A\u03b2PP-independent iA\u03b2 production and the pathways leading to their activation, and introduces the concept of conventional versus unconventional Alzheimer\u2019s 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.<\/jats:p>","DOI":"10.3390\/ijms25052981","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T10:11:57Z","timestamp":1709547117000},"page":"2981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["On the Inadequacy of the Current Transgenic Animal Models of Alzheimer\u2019s Disease: The Path Forward"],"prefix":"10.3390","volume":"25","author":[{"given":"Vladimir","family":"Volloch","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Rits-Volloch","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3233\/ADR-220031","article-title":"The Amyloid Cascade Hypothesis 2.0: On the possibility of once-in-a-lifetime-only treatment for prevention of Alzheimer\u2019s disease and for its potential cure at symptomatic stages","volume":"6","author":"Volloch","year":"2022","journal-title":"J. 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