The Amyloid Cascade Hypothesis 2.0: Generalization of the Concept

Abstract

Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the ACH. In the former, in contrast to the latter, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates, upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway, triggering a devastating second stage resulting in neuronal death. While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intra- rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD. Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" (sX) which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.

Keywords: Age-related cognitive decline; Alzheimer’s disease; Amyloid Cascade Hypothesis 2.0; BACE1 and BACE2 activators; amyloid-β protein precursor; intraneuronal amyloid-β.

Fig. 1

The generalized Amyloid Cascade Hypothesis 2.0 and the Engine that drives AD. Left Box (highlighted in gray): Life-long accumulation of AβPP-derived iAβ, through the cellular uptake of secreted peptide and intracellular retention of a fraction of AβPP-derived Aβ, to levels sufficient to ignite the AD “Engine” (rest of the figure). Middle Box: Several pathways, both actual (top two) and hypothetical (each line represent a pathway), of the Aβ-mediated elicitation of the integrated stress response or of yet unknown process capable of activating the cell-deleterious substance X (sX)-generating pathway. Top Box (highlighted in blue): Generation of intraneuronally retained sX. The yet to be determined sX is presumed to be capable of (a) anchoring a cascade that includes tau pathology and leads to neuronal death and (b) sustaining the activity of one or more pathways listed in the Middle Box, and thus perpetuating the feedback cycles and its own production. Right Box: sX rapidly accumulates intraneuronally; this sustains the operation of one or more of the AβPP-derived iAβ-mediated pathways shown in the Middle Box, which, in turn, support the generation of sX. It could be argued that the requirement that sX supports its own production is redundant in view of the continuous influx of AβPP-derived iAβ. However, this is not the case, because suppression of the AβPP proteolytic pathway at symptomatic stages of the disease in human trials had no effect whatsoever on the progression of AD [95, 96], consistent with the autonomous operation of the AD Engine. Blue and red arched arrows: Mutually propagating feedback cycles constituting an autonomous, self-perpetuating Engine that drives AD. One interesting and plausible special case of the generalized ACH2.0 is that of sX = (iAβ produced in the AβPP-independent pathway), where differentially derived iAβ runs both stages of AD. Crucially, iAβ produced independently of AβPP can be distinguished from that derived in the AβPP proteolysis, as described in the “Validation” section below. Confirmation of the occurrence of a type of iAβ originating independently of AβPP would equate it with and unequivocally establish the identity of sX.

Fig. 2

Dynamics of iAβ and/or sX accumulation in the affected neuronal population of an AD patient and progression of the disease. iAβ: Intraneuronal Aβ levels; sX: sX levels; T1: The level of AβPP = derived iAβ that triggers the elicitation of the ISR and activation of the AD Engine; T2: The level of iAβ or of sX that triggers cell’s commitment to the apoptotic pathway; Red blocks: Fraction of affected neurons either committed to apoptosis or dead; Vertical arrows: Indicate minimal fraction of neurons over the T2 threshold that causes symptomatic manifestation of AD. Blue lines: iAβ; Red lines: sX. Upper panels: Special ACH2.0 case with sX = (iAβ produced independently of AβPP). A) The initial symptomatic manifestation of the disease. The affected neurons reach and cross the T1 threshold within a narrow temporal window [2]; when the initial symptoms manifest, the T1 threshold has been crossed by and the AD Engine activated in all or the bulk of affected neuronal cells. B) Levels of iAβ cross the T2 threshold in a fraction of affected neurons (presumably all or most of affected neurons) sufficient to trigger the end-stage of the disease. Lower panels: ACH2.0 cases where sX is not iAβ. A’) The affected neurons cross the T1 threshold and activate the sX-generating pathway. When enough affected neurons cross the T2 threshold, AD symptoms manifest; by this time the sX production pathway has been initiated and the AD Engine activated in the bulk of affected neurons. B’) The end-stage of the disease. Note that in panels A’ and B’, the accumulation of iAβ and sX, shown above the T1 threshold, occurs in the same cells.

Fig. 3

Effect of the limited-duration iAβ depletion treatment, administered curatively or preventively, in AD. iAβ: Intraneuronal Aβ levels; sX: sX levels; T1: AβPP-derived iAβ level that triggers elicitation of the ISR and the activation of the AD Engine; T2: iAβ level that triggers cell’s commitment to the apoptotic pathway; Red blocks: Fraction of affected neurons committed to apoptosis or dead; Vertical arrows: Timing of the administration of iAβ depletion treatment; the drug is withdrawn after the complete or nearly complete depletion of iAβ is achieved. Upper panels (A–D): Treatments at different symptomatic stages in the special ACH2.0 case where sX = (iAβ produced independently of AβPP). A) The drug is administered at the early symptomatic stage of the disease. Levels of iAβ in surviving cells have been “reset” and the AD Engine switched off. The bulk of affected neurons, that did not yet reach the T2 threshold, recover and reconnect. At this point Aβ is produced only in the AβPP proteolytic pathway. The de novo accumulation of AβPP-derived iAβ resumes and, if its rate remains constant and linear pre- and post-treatment, iAβ levels are unlikely to reach the T1 threshold and the disease to recur within the remaining lifespan of an individual (at least in sporadic AD cases). B–D) The drug is administered at increasingly advanced stages of the disease. Outcomes are similar to that shown in panel A, except, as the disease progresses, there are less and less viable affected neurons that can be “reset” and thus redeemed. Lower panels: Preventive iAβ depletion therapy in the generalized ACH2.0. A’) Sporadic AD. The drug is administered in the early sixties; statistically prior to the late onset of the disease and before levels of AβPP-derived iAβ reach the T1 threshold in any neuronal cells. Levels of iAβ have been “reset”; the de novo accumulation of AβPP-derived iAβ to the T1 threshold would take decades and is unlikely to occur within the remaining lifespan of an individual. B’) Familial AD. The drug is administered in the early forties, and de-novo buildup of AβPP-derived iAβ to the T1 threshold could occur still within the lifespan of an individual; in such a case, a repeated administration of the drug could be required for the prevention of the disease. Note that the treatment (and its effects) depicted in A’ appear to be applicable to aging-related cognitive decline.