Targeting SPI1 to mitigate amyloid-β pathology in Alzheimer's disease

Spi-1 Proto-Oncogene (SPI1) is a transcription factor that plays a key role in the development of myeloid and B-lymphoid cells. ¹ Recently, SPI1 has been identified as a genetic risk factor for Alzheimer's disease (AD).^1,2 In vitro cell culture experiments have shown that SPI1 modulates the expression of AD-related genes involved in phagocytic activity and immune responses in microglia. ³ However, in vitro systems are limited in accurately replicating the intricate complexity of the brain and the crosstalk between its various cell types. ⁴ Consequently, the in vivo effects of SPI1 levels on AD pathology remain elusive. Additionally, a pivotal question is how to modulate the expression of SPI1 to achieve optimal therapeutic effects against AD and related diseases. Currently, there is not a clear consensus on whether SPI1 expression should be decreased or increased for therapeutic benefit. Thus, a better understanding of the in vivo effects of altering SPI1 expression will be necessary in order to pursue this as a therapeutic intervention for AD.

In a recent study, Kim et al. demonstrated that knocking down Spi1 in mice exacerbated the pathological features of AD, including Aβ aggregation, amyloid plaque accumulation, and gliosis (Figure 1). ⁵ In contrast, Spi1 overexpression in these mice had a protective effect. ⁵

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Figure 1.

Changes in Spi1 expression affect AD pathology. Spi1 knockdown exacerbated the pathological features of AD, including Aβ aggregation, amyloid plaque accumulation, astrogliosis, and microgliosis. In contrast, Spi1 overexpression reduced Aβ aggregation, amyloid plaque accumulation, gliosis, and axonal dystrophic neurites. Moreover, changes in Spi1 expression induce altered transcriptomic and cell-type-specific gene expression signatures.

The authors crossed Spi1-knockdown mice with APP/PS1 mice to investigate the role of Spi1 in AD. ⁵ They measured the levels of insoluble Aβ₄₀ and Aβ₄₂ in the brains of four-month-old mice that were either wild-type or hemizygous in respect to Spi1 (Spi1^+/+/APP/PS1 and Spi1^+/−/APP/PS1). ⁵ When Spi1 was knocked down, Aβ₄₀ and Aβ₄₂ levels in the cortex and hippocampal regions significantly increased. This suggests that Spi1 may play a role in inhibiting Aβ accumulation during the development of AD. The authors further evaluated amyloid plaque deposition in the mouse brains and found that the amyloid plaque load, number, and fibrillar plaque deposition in the cortex and hippocampus increased in the Spi1-knockdown mice. Furthermore, the reduction in Spi1 expression exacerbated microgliosis and astrogliosis in the Aβ amyloidosis mouse model. On the other hand, overexpression of Spi1 significantly reduced Aβ accumulation, amyloid plaque load, and number in the cerebral cortex and hippocampus of both female and male 5XFAD mice. ⁵ This suggests that increased Spi1 expression may help to reduce pathologic features of AD. These findings further confirm the critical role of SPI1 in regulating Aβ accumulation and amyloid plaque formation.

To gain a deeper understanding of the underlying mechanisms, the same study also analyzed the gene expression profiles of Spi1 knockout and wild-type mice, identifying 26 differentially expressed genes (DEGs) involved in multiple biological pathways. ⁵ Pathway enrichment analysis of the DEGs using Enrichr emphasized microglial cell pathways, while MetaCore analysis specifically identified “MHC Class I” as the most significantly enriched pathway. This study also employed NanoString transcriptomic analysis of the cerebral cortex of an AD mouse model (5XFAD) crossed with transgenic Spi1-overexpressing mice (Spi^tg/0) to investigate the role of Spi1 in AD pathogenesis. ⁵ Compared to Spi1^+/+/5XFAD mice, Spi1-overexpressing Spi1^Tg/0/5XFAD mice displayed significant downregulation of C1qa, Fcer1g, Tyrobp, Trem2, Cyba, Ctss, and Laptm5 mRNA levels, while Hspa1b was upregulated. Expression changes in these genes may reflect inflammatory and neurotoxic responses to AD pathology. Notably, Spi1 was linked to pathways involved in classical complement system activation and immune response, as well as oxidative stress-related processes. Functional analysis revealed that Spi1 knockout reduced microglial response to Aβ plaques, while Spi1 overexpression did not significantly affect plaque coverage. Moreover, overexpression of Spi1 reduced the abundance of LAMP1-positive plaques and associated clusters in the cortex and hippocampus of AD mice, suggesting reduced neuronal toxicity. Single-cell RNA sequencing further demonstrated that Spi1 overexpression in astrocytes, neurons, and microglia significantly altered gene expression patterns related to neurodegenerative diseases, highlighting the complex role of Spi1 in AD pathogenesis.

This study by Kim et al. has addressed the need for using in vivo model systems to explore the role of Spi1 in AD pathogenesis. ⁵ The findings of this study are critical for understanding the role of Spi1 in AD pathology and challenge the previous view that Spi1 inhibition may be beneficial in AD. ⁶ Previously, the prevailing idea was that inhibiting Spi1 expression would protect against AD pathology, primarily based on observed correlations between Spi1 expression levels and the severity of AD-related features. ⁶ However, findings by Kim et al. challenge this perspective, demonstrating that Spi1 knockdown exacerbates pathological features, such as Aβ aggregation and gliosis. This highlights a critical distinction: while lower Spi1 expression has been associated with decreased AD risk in previous study, ⁶ the findings by Kim et al. underscore that such associations do not necessarily imply causation. ⁵ The study provides compelling evidence that altering Spi1 levels through either knockdown or overexpression directly impacts AD pathology, suggesting a more nuanced role for Spi1 that warrants further investigation.

This study also highlights the impact of Spi1 on microglia function, which is crucial in regulating immune response, complement system, and phagocytic clearance in AD. ⁷ The study further reveals that decreasing Spi1 expression aggravates AD-related pathological features, whereas increasing Spi1 expression ameliorates these phenomena and dystrophic neurites. This underscores the potential of Spi1 as a therapeutic target, offering new insights into AD understanding and treatment.

However, there are aspects worthy of further consideration. Firstly, the current research primarily focuses on a specific age group of mice, which may not comprehensively reflect the dynamic role of Spi1 throughout AD progression. Future studies could expand the age range from early-stage to late-stage mice to gain a comprehensive understanding of Spi1's dynamic function in the entire AD course.^8,9 Additionally, future studies could also attempt to validate the role and mechanism of SPI1 in human AD patient samples. Collection of blood or cerebrospinal fluid from AD patients or cadaveric brain tissue samples would allow for the detection of SPI1 expression levels and related gene expression changes, thus verifying whether the results obtained in mouse models are applicable to humans. ¹⁰ Moreover, the interaction of SPI1 with other known AD risk genes including MEF2C, GAB2, ABCC11, and ATCG1 should also be explored further. ¹¹