Description
Age-related macular degeneration (AMD) and Alzheimer’s disease (AD) are both severe age-related disorders that are the leading causes of vision loss and dementia in older adults, respectively. The diseases share similar risk profiles; ageing, smoking, and cardiovascular dysfunction, as well as similar pathologic processes; chronic inflammation, lysosome dysfunction and amyloid accumulation. Because of this, a key research area focuses on the diseases in tandem to identify whether there are common molecular/cellular mechanisms and thus whether treatments could be used to alleviate symptoms of both disorders. Our study extends this research in an unbiased genome-wide approach by directly comparing bulk-RNAseq data derived from AMD iPSC-macrophages with common pathways and genes associated with AD. Key genes identified through network co-expression analysis were then studied further in human microglial cell (HMC3) and iPSC-microglial cultures, to discern the effect of activation via different immunomodulatory regulators that induce AD-related pathological responses. As well as this, we knocked down the immune gene, CD74, to investigate the functional effects of CD74 on expression of key disease-associated genes associated with different immune microglial processes. Our findings implicate lysosome dysfunction and degradation of the extracellular matrix as key drivers in AMD pathology. As well as this, AMD disease-associated genes overlapped with key genes implicated in the disease-associated microglial (DAM) state which has been previously linked to AD, thus highlighting a critical role of immune cell dysfunction in AMD, and pointing to shared pathological drivers. However, we did not find critical overlap between macrophage activation state and disease, despite the association with disease-associated microglia. Finally, key risk genes TNF, CD33 and HEXB were found to functionally rely on the immune response of CD74 to protect against the impact of pro-inflammatory activators. Further studies should make use of CRISPR gene editing to discern the causal directional effect of key gene dysfunction within these AMD and AD pathologies. Collectively this work identifies new genes, pathways and processes involved in AMD, and some shared with AD, which may provide opportunities for new drug discovery research, or alternative methods to develop biomarkers to track disease stages better.
Lay Abstract
Age-related macular degeneration (AMD) and Alzheimer’s disease (AD) are severe disorders that are leading causes of vision loss and cognitive decline in older people respectively. They share a common risk profile (ageing, smoking, cardiovascular dysfunction), and similar pathological mechanisms, such as inflammation, amyloid accumulation and lysosome dysfunction.
We aimed to study both diseases in tandem to identify common genetic risks and cellular mechanisms, to develop our understanding and contribute towards treatment that targets both pathologies.
We identified key genetic drivers in AMD iPSC-macrophages and compared these with key genes and pathways in AD. Key genes that were found to be associated with AMD were studied in human microglial cell (HMC3) and iPSC-microglial cultures, to discern the effect of activation via different immunomodulatory regulators that induce AD-related pathological responses.
Our findings implicate lysosome dysfunction and degradation of the extracellular matrix as key drivers in AMD. Additionally, AMD disease-associated genes overlapped with key genes implicated in the disease-associated microglial (DAM) state which has been previously linked to AD, highlighting a critical role of immune cell dysfunction in AMD, and pointing to shared pathological drivers. However, we did not find overlap between macrophage activation state and disease, despite the association with disease-associated microglia.
| Lay Title | Investigating common risk genes and molecular mechanisms in age-related macular degeneration and Alzheimer’s disease |
|---|---|
| Role | Master Student |