Alzheimer’s Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory DOI Open Access

Vladimir Volloch,

Sophia Rits‐Volloch

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4252 - 4252

Published: April 29, 2025

The present Perspective analyzes the remarkable evolution of Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory Alzheimer’s disease (AD) since its inception a few years ago, as reflected in diminishing role amyloid-beta (Aβ) disease. In initial iteration ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. ISR, turn, activates AβPP-independent production C99 fragment that is processed into iAβ, which drives second ACH2.0 stemmed from realization AD is, fact, sustained ISR. It introduced two categories AD—conventional and unconventional—differing mainly manner their causation. former caused by ISR triggered AβPP-derived whereas latter, elicited stressors distinct iAβ arising brain trauma, viral bacterial infections, various types inflammation. Moreover, conventional always contains an unconventional component, both forms, driven generated independently AβPP. third, current, iteration, posits proteolytic suppressed AD-affected neurons Suppression seems oxymoron: equated with AD, later inconceivable without ingrained (ACH)-based notion. But suppression where logic leads, follow it we only need overcome inertia preexisting assumptions. not generation suppressed, so all components AβPP pathway. This assertion quantum leap (unless overcoming counts such): global cellular protein synthesis severely under conditions, there no reason for constituents pathway be exempted, they, apparently, are not, indicated empirical data. contrast, tau translation persists conditions because human mRNA internal ribosomal entry site 5′UTR. current mouse models, derived expressed exogenously transgenes elicits thus suppresses own production. Its levels cannot principally reach pathology-causing regardless number or FAD mutations they (or additional transgenes) carry. Since inoperative mice, transgenic models have potential developing full spectrum pathology. What display effects iAβ-elicited paper describes strategies construct adequate models. also details utilization cells model system currently available final alteration Perspective, AβPP, supports functionality viability, after all, potentially produced neurons, albeit conventionally but ISR-driven -compatible process. Thus, narrative begins “omnipotent” capable triggering driving ends up this peptide largely dislodged pedestal retaining central one, although prevalent (conventional), category (and none). Among interesting inferences determination “sporadic AD” sporadic at (“non-familial” would much better designation). term has fatalistic connotations, implying can strike random. patently case: affects subpopulation, basis well understood. Another conclusion that, unless prevented, occurrence inevitable given sufficiently long lifespan. defines therapeutic directions taken auspicious ways forward. includes ACH-based drugs (those interfering and/or depleting extracellular Aβ). They legitimate (albeit inefficient) preventive agents There however, proverbial snowball’s chance hell them being effective symptomatic lecanemab, donanemab, any other “…mab” “…stat” notwithstanding. comprise Aβ-specific antibodies, inhibitors beta- gamma-secretase, modulators latter. latter category, among go following: (1) Depletion which, if “deep”, opens tantalizing possibility once-in-a-lifetime transient treatment aging-associated cognitive decline, AACD. (2) Composite therapy comprising degradation C99/iAβ concurrent inhibition A single could sufficient arrest progression prevent recurrence life. Multiple recurrent treatments achieve same outcome Alternatively, reduction/removal ISR-eliciting through elimination source convert preventable/treatable administration composite depletion/ISR therapy. Efficient suitable available, explicitly clear look C99/iAβ-specific targeted agents—activators BACE1 and, especially, BACE2. Directly acting such proteolysis-targeting chimeras (PROTACs) molecular-glue degraders (MGDs) viable options. (3) circumscribed shift (either upstream downstream) position transcription start (TSS) gene, or, alternatively, gene editing-mediated excision replacement small, defined segment portion encoding 5′-untranslated region mRNA; targeting RNA anti-antisense oligonucleotides another possibility. If properly executed, these RNA-based interfere protein-coding mRNA, each preventing stopping either arresting forms. interspersed “validation” sections: every conceptually significant notion validated existing data experimental procedure validating proposed.

Language: Английский

Alzheimer’s Is a Multiform Disease of Sustained Neuronal Integrated Stress Response Driven by the C99 Fragment Generated Independently of AβPP; Proteolytic Production of Aβ Is Suppressed in AD-Affected Neurons: Evolution of a Theory DOI Open Access

Vladimir Volloch,

Sophia Rits‐Volloch

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4252 - 4252

Published: April 29, 2025

The present Perspective analyzes the remarkable evolution of Amyloid Cascade Hypothesis 2.0 (ACH2.0) theory Alzheimer’s disease (AD) since its inception a few years ago, as reflected in diminishing role amyloid-beta (Aβ) disease. In initial iteration ACH2.0, Aβ-protein-precursor (AβPP)-derived intraneuronal Aβ (iAβ), accumulated to neuronal integrated stress response (ISR)-eliciting levels, triggers AD. ISR, turn, activates AβPP-independent production C99 fragment that is processed into iAβ, which drives second ACH2.0 stemmed from realization AD is, fact, sustained ISR. It introduced two categories AD—conventional and unconventional—differing mainly manner their causation. former caused by ISR triggered AβPP-derived whereas latter, elicited stressors distinct iAβ arising brain trauma, viral bacterial infections, various types inflammation. Moreover, conventional always contains an unconventional component, both forms, driven generated independently AβPP. third, current, iteration, posits proteolytic suppressed AD-affected neurons Suppression seems oxymoron: equated with AD, later inconceivable without ingrained (ACH)-based notion. But suppression where logic leads, follow it we only need overcome inertia preexisting assumptions. not generation suppressed, so all components AβPP pathway. This assertion quantum leap (unless overcoming counts such): global cellular protein synthesis severely under conditions, there no reason for constituents pathway be exempted, they, apparently, are not, indicated empirical data. contrast, tau translation persists conditions because human mRNA internal ribosomal entry site 5′UTR. current mouse models, derived expressed exogenously transgenes elicits thus suppresses own production. Its levels cannot principally reach pathology-causing regardless number or FAD mutations they (or additional transgenes) carry. Since inoperative mice, transgenic models have potential developing full spectrum pathology. What display effects iAβ-elicited paper describes strategies construct adequate models. also details utilization cells model system currently available final alteration Perspective, AβPP, supports functionality viability, after all, potentially produced neurons, albeit conventionally but ISR-driven -compatible process. Thus, narrative begins “omnipotent” capable triggering driving ends up this peptide largely dislodged pedestal retaining central one, although prevalent (conventional), category (and none). Among interesting inferences determination “sporadic AD” sporadic at (“non-familial” would much better designation). term has fatalistic connotations, implying can strike random. patently case: affects subpopulation, basis well understood. Another conclusion that, unless prevented, occurrence inevitable given sufficiently long lifespan. defines therapeutic directions taken auspicious ways forward. includes ACH-based drugs (those interfering and/or depleting extracellular Aβ). They legitimate (albeit inefficient) preventive agents There however, proverbial snowball’s chance hell them being effective symptomatic lecanemab, donanemab, any other “…mab” “…stat” notwithstanding. comprise Aβ-specific antibodies, inhibitors beta- gamma-secretase, modulators latter. latter category, among go following: (1) Depletion which, if “deep”, opens tantalizing possibility once-in-a-lifetime transient treatment aging-associated cognitive decline, AACD. (2) Composite therapy comprising degradation C99/iAβ concurrent inhibition A single could sufficient arrest progression prevent recurrence life. Multiple recurrent treatments achieve same outcome Alternatively, reduction/removal ISR-eliciting through elimination source convert preventable/treatable administration composite depletion/ISR therapy. Efficient suitable available, explicitly clear look C99/iAβ-specific targeted agents—activators BACE1 and, especially, BACE2. Directly acting such proteolysis-targeting chimeras (PROTACs) molecular-glue degraders (MGDs) viable options. (3) circumscribed shift (either upstream downstream) position transcription start (TSS) gene, or, alternatively, gene editing-mediated excision replacement small, defined segment portion encoding 5′-untranslated region mRNA; targeting RNA anti-antisense oligonucleotides another possibility. If properly executed, these RNA-based interfere protein-coding mRNA, each preventing stopping either arresting forms. interspersed “validation” sections: every conceptually significant notion validated existing data experimental procedure validating proposed.

Language: Английский

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