The Amyloid Cascade Hypothesis 2.0: On the Possibility of Once-in-a-Lifetime-Only Treatment for Prevention of Alzheimer's Disease and for Its Potential Cure at Symptomatic Stages

Abstract

We posit that Alzheimer's disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal-Aβ (iAβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived iAβ triggers relatively benign cascade that activates the AβPP-independent iAβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent iAβ-generating pathway is retained intraneuronally and perpetuates the pathway's operation. This process constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its iAβ contribution to insignificant, and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine's components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the iAβ population and 'reset' its levels below those required for the operation of the AD Engine. Any sufficiently selective iAβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the 'common' pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread 'resilience to AD' phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform.

Keywords: AβPP-independent generation of iAβ; BACE activators as AD drugs; PKR and HRI kinases; iAβ depletion therapy for AD; integrated stress response; intraneuronal Aβ (iAβ); the Amyloid Cascade Hypothesis 2.0.

Fig. 1

Amyloid Cascade Hypothesis 2.0: The engine that drives AD; Etiology and primum mobile of the disease in the proposed AD paradigm. ACH2.0 defines a tandem, Aβ-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived Aβ triggers relatively benign cascade (left to middle boxes) that activates the AβPP-independent pathway generating intraneuronally-retained Aβ, which, in turn, initiates the second, devastating cascade that is driven by the AD Engine, includes tau pathology, and ultimately leads to the neuronal loss. Left Box (highlighted in grey): The “Starter Motor” – 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 represents a pathway), of the Aβ-mediated elicitation of the integrated stress response or of yet unknown process capable of activating the AβPP-independent iAβ production pathway. Top Box (highlighted in blue): AβPP-independent generation of iAβ via one of the following mechanisms— RNA-dependent AβPP mRNA amplification; the internal initiation of transcription within the AβPP gene; cleavage within AβPP mRNA; the internal initiation of translation within intact AβPP mRNA. It cannot be excluded that yet another, unforeseen, mechanism underlies the AβPP-independent iAβ generation pathway. Regardless of the mechanism employed, translation initiates at the AUG normally encoding Met671 of AβPP (which contiguously precedes Asp1 of C99 and of Aβ) and results in C100 (N-terminal Met-containing C99, converted post-translationally into C99), which is processed by γ-secretase cleavage into Aβ (or Met-Aβ eventually converted to Aβ) that is retained intraneuronally. Right Box: The entire output, or at least the bulk of Aβ generated in the AβPP-independent pathway is retained within the cell, and the iAβ levels rapidly increase. This sustains the operation of one or more of the iAβ-mediated pathways shown in the Middle Box, which, in turn, support the AβPP-independent generation of iAβ. Blue and red arched arrows: Mutually perpetuating feedback cycles. They constitute an autonomous, self-sustained, two-stroke engine, the engine that drives AD. The disease commences and manifests symptomatically only following the activation of the AD Engine.

Fig. 2

Dynamics of Aβ accumulation and the disease in AD-affected patients: Two paradigms. Images on the left: Dynamics of Aβ accumulation (extracellular in A and B, intraneuronal in C-E); Images on the right: Dynamics of neurodegeneration. Blue lines: Levels of Aβ; Red lines: Extent of neurodegeneration; Black lines: Indicator lines, no noticeable neurodegeneration; Red blocks: Symptomatic manifestation of AD. T: Threshold of extracellular Aβ levels and the corresponding extent of cell damage triggering AD symptoms; T1: Threshold of AβPP-derived iAβ levels required for the activation of the AβPP-independent iAβ production pathway (genetic aspects and epigenetic factors influence the timing of the T and T1 crossings, hence the fanning lines); T2: Threshold of iAβ levels and the corresponding extent of neuronal damage triggering AD symptoms (T, T1, and T2 are patient-specific). A (SAD ), B (FAD): Dynamics of AD in the old paradigm. Levels of extracellular Aβ increase and so does the extent of neurodegeneration; when the T is reached, AD symptoms manifest. C (SAD), D (FAD): Dynamics of AD in the new paradigm. As AβPP-derived iAβ cross the T1, AβPP-independent production of iAβ is activated and its levels rapidly increase. After a lag period during which iAβ further accumulates, neurodegeneration commences; when the T2 is reached, AD symptoms manifest. Red and blue lines over the T1 threshold are shown arbitrarily as parallel (i.e., identical rates of the accumulation of iAβ produced independently of AβPP and of the corresponding extent of cellular damage) and as of uniform heights over the T2 threshold (i.e., equal extents of damage); in reality, both the rates and the extents and, accordingly, lines’ angles and their heights over the T2 are likely different and define the duration of the disease in individual AD patients. E: Presumed dynamics of iAβ accumulation in subjects with an inoperative AD Engine. AβPP-derived iAβ levels cross the T1 threshold but the AβPP-independent iAβ production pathway is not activated. Neither neurodegeneration-triggering iAβ levels nor the T2 threshold are reached; there is no noticeable neurodegeneration, no AD symptoms manifest, no disease occurs.

Fig. 3

Dynamics of iAβ accumulation and the disease in the affected neuronal population of an AD patient. iA β: Intraneuronal Aβ levels; T1: The level of iAβ that triggers elicitation of the integrated stress response, initiation of AβPP-independent generation of iAβ, and activation of the AD Engine; T2: The level of iAβ 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. A: The initial symptomatic manifestation of the disease. The affected neurons cross the T1 threshold stochastically in a wide temporal window; at the time when the initial symptoms manifest, a substantial fraction of affected neurons did not yet cross the T1 threshold. B: The end-stage of the disease. A’: The initial symptomatic manifestation of the disease. The affected neurons reach and cross the T1 threshold within a narrow temporal window; when the initial symptoms manifest, the T1 threshold has been crossed by and the AD Engine has been activated in all or the bulk of affected neuronal cells. B’: The end-stage of the disease. Of the two, only the scenario depicted in A’ and B’ is viable since it conforms (unlike the scenario shown in A and B) to experimental data.

Fig. 4

Effect of iAβ depletion treatment administered for limited duration at different symptomatic stages of AD. iA β: Intraneuronal Aβ levels; T1: iAβ level that triggers elicitation of the integrated stress response, initiation of AβPP-independent generation of iAβ, and 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 a treatment; the drug is withdrawn after the complete or nearly complete depletion of iAβ is achieved. 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, which 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 via cellular uptake of secreted peptide and intracellular retention of a fraction of its output in the AβPP proteolytic pathway. If the rate of accumulation remains constant and linear pre- and post-treatment (other options are considered below), the levels of AβPP-derived iAβ are unlikely to reach the T1 threshold and the disease to recur within the remaining lifespan of an individual (at least in SAD cases). B-D: The drug is administered at increasingly advanced stages of the disease. Outcomes are similar to that shown in A, except, as the disease progresses, there are less and less viable affected neurons that can be “reset” and thus redeemed.

Fig. 5

Effect of iAβ depletion by a treatment of limited duration prior to symptomatic manifestation of AD. iA β: Intraneuronal Aβ levels; T1: iAβ level that triggers elicitation of the integrated stress response, initiation of AβPP-independent generation of iAβ, and activation of the AD Engine; T2: iAβ level that triggers cell’s commitment to the apoptotic pathway; Vertical arrows: timing of the administration of a treatment; the drug is withdrawn after the complete or nearly complete depletion of iAβ is achieved. A: Prevention of SAD. The drug is administered in the early sixties; statistically prior to the late onset of the disease and before levels of intracellular AβPP-derived iAβ reach the T1 threshold in any neuronal cells. Levels of iAβ have been ‘reset’ and the de novo accumulation of AβPP-derived iAβ resumes via the cellular uptake of secreted peptide and the intracellular retention of a fraction of its output in the AβPP proteolytic pathway. If the rate of this accumulation remains constant and linear through the lifespan of a neuron (other options are described in the Discussion section below), the levels of AβPP-derived iAβ are unlikely to reach the T1 threshold and the disease to occur within the remaining lifespan of an individual. B: Prevention of FAD. The drug is administered in the early forties, statistically prior to the early onset of the disease and before any neurons reach the T1 threshold. Levels of AβPP-derived iAβ are reset and their restoration would take decades. This 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 AD.