β2-microglobulin: An essential coaggregation factor with β-amyloid in amyloid pathology

Abstract

Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disease characterized by cognitive deficits, β-amyloid (Aβ) accumulation-induced amyloid plaques, and tau hyperphosphorylation-induced neurofibrillary tangles.¹ Interestingly, emerging evidence suggests other factors may contribute to Aβ-associated pathologies.² β2-microglobulin (β2M), one of the major histocompatibility complex class I molecules, is a short peptide with seven antiparallel β-strands. It is elevated in AD brains and has recently been detected in the amyloid plaque core.³ Therefore, increasing evidence suggests β2M may be a potential factor that promotes Aβ aggregation and neurotoxicity.

A recent study in Nature Neuroscience conducted by Zhao et al. found that β2M may be a possible factor involved in amyloid pathologies.³ The authors characterized the pathological changes of β2M and elucidated the functional involvement of β2M in amyloid deposition and spreading and in boosting Aβ neurotoxicity.³ They concluded that β2M is an essential coaggregation factor with Aβ in amyloid pathology and β2M-Aβ coaggregation is a therapeutic target for AD. In addition, their findings indirectly support the amyloid hypothesis and provide additional information underlying Aβ aggregation and Aβ neurotoxicity. In the past 2 decades, all clinical trials based on the amyloid hypothesis on AD have failed, prompting reconsideration of the amyloid hypothesis.³ However, the current study performed by Zhao et al. confirmed that inhibition of Aβ deposition significantly improves cognitive function, indirectly supporting this hypothesis. More importantly, their findings revealed that β2M expressed in the central nervous system and peripheral tissues are potential targets for alleviating amyloid pathology and Aβ neurotoxicity. Disrupting the β2M-Aβ interactions ameliorated Aβ deposition and Aβ-associated pathogenesis, exhibiting a tremendous therapeutic potential for AD treatment. Overall, although Zhao et al. cannot exclude the possibility that MHC class I contributes to β2M-dependent neurotoxicity, their study identifies a previously undefined role of β2M in Aβ aggregation and neurotoxicity and offers a novel therapeutic strategy for AD by inhibiting peripheral β2M (Figure 1).

Meanwhile, their findings also raise several intriguing questions that deserve further investigation. First, Zhao et al. discovered β2M is mainly present in microglia, suggesting it would be interesting to study further the relationship between microglial β2M and microglial function. For example, it is of great interest to investigate the role of β2M in microglial-mediated phagocytosis, synapse pruning, and neuroinflammatory response in AD and other brain disorders. Moreover, single-cell technologies have found various phenotypes of microglia.^{4, 5} Therefore, the relationship between microglial phenotypes and β2M remains unclear and deserves further investigation. Second, Zhao et al. demonstrated that blocking β2M or β2M-Aβ coaggregation reduces Aβ aggregation and deposition.³ However, whether the disrupted β2M-Aβ interaction is accompanied by enhanced Aβ clearance through the glymphatic system is unknown. Microglia and astrocytes are intimately related, and the microglial β2M may cause changes in astrocyte functions and phenotypes, including polarized distribution of aquaporin-4 in astrocytes. Third, brain injuries are risk factors for AD. For example, stroke and repeated closed head injury increase neurotoxic Aβ accumulation and impair the balance between Aβ production and clearance. In the current study, Zhao et al. observed the essential role of microglial and peripheral β2M in AD. Therefore, it is worthwhile to examine the changes in microglial and peripheral β2M in stroke and brain injury, wherein microglia are activated and involved in the progression of brain injury. According to a previous study, β2M knockdown significantly alleviated tau pathologies in primary mouse neurons and the tau-P301S overexpression mouse model. However, different from the findings in the current study, the effects of β2M deletion in reducing tau pathology were MHC-dependent. Therefore, more studies are needed to investigate the reasons for this difference. Finally, it is critical to decipher further how β2M interacts with Aβ to promote Aβ neurotoxicity. Fully understanding the mechanism underlying β2M-Aβ interaction and the structural changes of β2M and Aβ in boosting neurotoxicity would help to develop therapies for AD targeting β2M-Aβ coaggregation.

Chongyun Wu: Funding acquisition and writing—original draft. Timon Cheng-Yi Liu: Funding acquisition and writing—review & editing. Rui Duan: Funding acquisition. Luodan Yang: Funding acquisition, supervision, writing—review & editing.

The authors declare no conflict of interest in this study.

The ethics approval was not needed in this study.