Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
Int J Mol Sci. 2023 Jul 31;24(15):12246. doi: 10.3390/ijms241512246.
With the long-standing amyloid cascade hypothesis (ACH) largely discredited, there is an acute need for a new all-encompassing interpretation of Alzheimer's disease (AD). Whereas such a recently proposed theory of AD is designated ACH2.0, its commonality with the ACH is limited to the recognition of the centrality of amyloid-β (Aβ) in the disease, necessitated by the observation that AD-causing mutations affect, in one way or another, Aβ. Yet, even this narrow commonality is superficial since AD-causing Aβ of the ACH differs distinctly from that specified in the ACH2.0: Whereas in the former, the disease is caused by secreted extracellular Aβ, in the latter, it is triggered by Aβ-protein-precursor (AβPP)-derived Aβ (Aβ) and driven by Aβ generated of AβPP. The ACH2.0 envisions AD as a two-stage disorder. The first, asymptomatic stage is a decades-long accumulation of AβPP-derived Aβ, which occurs via internalization of secreted Aβ and through intracellular retention of a fraction of Aβ produced by AβPP proteolysis. When AβPP-derived Aβ reaches critical levels, it activates a self-perpetuating AβPP-independent production of Aβ that drives the second, devastating AD stage, a cascade that includes tau pathology and culminates in neuronal loss. The present study analyzes the dynamics of Aβ accumulation in health and disease and concludes that it is the prime factor driving both AD and aging-associated cognitive decline (AACD). It discusses mechanisms potentially involved in AβPP-independent generation of Aβ, provides mechanistic interpretations for all principal aspects of AD and AACD including the protective effect of the Icelandic AβPP mutation, the early onset of FAD and the sequential manifestation of AD pathology in defined regions of the affected brain, and explains why current mouse AD models are neither adequate nor suitable. It posits that while drugs affecting the accumulation of AβPP-derived Aβ can be effective only protectively for AD, the targeted degradation of Aβ is the best therapeutic strategy for both prevention and effective treatment of AD and AACD. It also proposes potential Aβ-degrading drugs.
随着长期存在的淀粉样蛋白级联假说（ACH）受到广泛质疑，现在迫切需要一种新的、全面的阿尔茨海默病（AD）解释。虽然最近提出的 AD 理论被指定为 ACH2.0，但它与 ACH 的共同之处仅限于认识到淀粉样蛋白-β（Aβ）在疾病中的核心地位，这是由这样一个观察结果所必需的，即 AD 致病突变以这样或那样的方式影响 Aβ。然而，即使这种狭隘的共性也是表面的，因为 ACH 中的 AD 致病 Aβ与 ACH2.0 中指定的 Aβ明显不同：ACH 中，疾病是由分泌的细胞外 Aβ引起的，而后者则是由 Aβ 蛋白前体（AβPP）衍生的 Aβ（Aβ）触发的，并由 AβPP 生成的 Aβ 驱动。ACH2.0 将 AD 视为一种两阶段疾病。第一阶段是无症状阶段，这是长达数十年的 AβPP 衍生 Aβ的积累，通过分泌的 Aβ内化和 AβPP 蛋白水解产生的 Aβ的一部分在细胞内保留来发生。当 AβPP 衍生的 Aβ达到临界水平时，它会激活自我维持的 AβPP 独立产生的 Aβ，从而驱动第二阶段的破坏性 AD 阶段，这一级联包括 tau 病理学，并最终导致神经元丧失。本研究分析了 Aβ在健康和疾病中的积累动态，并得出结论，它是驱动 AD 和与衰老相关的认知能力下降（AACD）的主要因素。它讨论了可能涉及 AβPP 独立产生 Aβ的机制，为 AD 和 AACD 的所有主要方面提供了机制解释，包括冰岛 AβPP 突变的保护作用、早发性 FAD 和受影响大脑中特定区域 AD 病理学的顺序表现，并解释了为什么当前的小鼠 AD 模型既不充分也不合适。它假设，虽然影响 AβPP 衍生 Aβ积累的药物仅对 AD 具有保护作用，但靶向降解 Aβ是预防和有效治疗 AD 和 AACD 的最佳治疗策略。它还提出了潜在的 Aβ 降解药物。
