2024 年 10 巻 p. 15-17
Alzheimer’s disease (AD) is a common cause of dementia, characterized by progressive memory loss and various functional impairments in the brain. Amyloid β-proteins (Aβ) is a main component of senile plaques, which is a major pathological features of AD. According to the amyloid cascade hypothesis, the deposition of Aβ in the brain is a key stone of the pathogenesis of AD. During the past decade, several Aβ-targetted medications have been developed, and the clinical trials for AD have been performed so far. In this article, we summarize the clinical features of AD and the molecular mechanisms of Aβ. In addition, we focus a content about the transmissible potencies of Aβ pathology and the inactivation methods against Aβ aggregates to prevent the transmission of Aβ among individuals.
Alzheimer’s disease (AD) is a common cause of dementia in elderly people. Progressive memory loss is a principal symptom of AD. According to the amyloid cascade hypothesis, accumulation of amyloid β-proteins (Aβ) is a primary event of AD pathogenesis1). During the dacade, several clinical trials of the anti-Aβ monoclonal antibodies for AD patients have been performed2). In this article, we will review the clinical features of AD, and summarize the essences of the molecular and biological characteristics of Aβ.
AD is a progressive neurodegenerative disorder that has been known as the reprensetative cause of dementia. The main clinical manufestations of AD are progressive memory loss and functional impairment in the brain3,4). The pathological features of AD are extracellular deposition of Aβ plaques (senile plaques) and intracellular aggregations of neurofibrillary tangles5). Based on the amyloid cascade hypothesis, the deposition of Aβ plaques in the brain is the first event of AD that triggers tau pathology and neuronal death, leading to the cognitive impairment1).
Aβ is a major component of senile plaques5). The most common forms of Aβ are Aβ40 and Aβ42. Aβ42 is highly neurotoxic and can easily form Aβ42 aggregates6). During the Aβ aggregation process, Aβ shows various species including low-molecular-weight oligomers, high-molecular-weight (HMW) oligomers, and protofibrils7,8) (Fig. 1). Among the Aβ species, Aβ oligomers are widely regarded as the most toxic form of Aβ9). The Osaka familial AD mutation of Aβ (E693Δ) have reported to show extremely low levels of senile plaques with the elevated cerebrospinal fluid levels of Aβ oligomers10,11).
During the nucleation phase of the amyloid β-proteins (Aβ) aggregation process, the intermediate molecules including low molecular weight oligomer, high molecular weight oligomer are formed from Aβ monomers. After nucleation, hyperbolic fibril formations are facilitated, leading to the development of mature fibrils. The intraparenchymal deposition of the Aβ plaques derived from mature fibrils (senile plaques) results to the neurodegenerative changes in Alzheimer’s disease.
We have observed the fibrillar elongation of Aβ aggregates using high-speed atomic force microscopy (HS-AFM), which can observe the structural dynamics of proteins and other biomicromolecules directly in the single fiber levels12–17). Continuous observations of Aβ42 aggregates using HS-AFM revealed that fibrillar structures of Aβ42 aggregates had different structures, including straight, spiral and hybrid patterns with swiching features13). In addition, we realed that the fibrillar formation were not observed during the incubation of HMW Aβ42, indicating that HMW Aβ42 would not have potencies to form Aβ aggregates13). Recently, we successed the continuos observations of dynamics of Aβ42 protofibrils, and revealed the precise interactions of Aβ42 protofibrils and lecanemab at the single-molecule levels using HS-AFM17).
Previous studies reported that Aβ pathology can propagate among individuals through neurosurgical procedurres and human cadaveric tissues-derived drug injections18–20). The developments of inactivation methods against Aβ propagation is critical to prevent iatrogenic transmission of Aβ pathology. Our previous studies revealed that seeding activity of Aβ aggregates was inactivated by autoclave (AC)12). The results of the circular dichroism spectroscopy demonstrated that AC reduced β-sheet structures in Aβ aggregates12). We speculated that decreasing β-sheet structures in Aβ aggregates could inactivate the seeding activity of Aβ aggregates.
Comprehensive researches have been conducted to clarify the essential pathogenesis of AD worldwide. The evolutional developments of diagnostic/therapeutic materials for AD patients have been needed. Approach to the clarifications of the pathogenesis of AD will progressed for the development of more effective treatments to cure AD patients.
The authors thank Dr Masahito Yamada (Divition of Neurology, Department of Internal Medicine, Kudanzaka Hospital) for providing supports for our previous research.
The authors have no conflicts of interest.
