Columbia University discovers new target for frontotemporal dementia treatment

Frontotemporal dementia (FTD) is a group of dementia syndromes characterized by frontotemporal lobe atrophy. In the early stage, personality changes will occur, and patients will become irritable, stubborn, indifferent and depressed. Abnormal behavior will gradually appear, including inappropriate behavior, slow reaction, amnesia, aphasia, putting everything in the mouth to test, poor vocabulary and fragmentary delusions. The peak age of onset is 60 years old, mostly in women. Due to the complex pathogenesis, there is currently no good treatment, and the disease can only be slowed down by drugs or cognitive training. About half of the patients will have large areas of hyperphosphorylated tau (p-tau) deposition in various areas of the brain. And about half of the patients have a family history of the disease, and 10%-30% of these patients carry autosomal dominant mutations in the MAPT gene (encoding Tau protein).

Recently, Gunnar Hargus' research team from the Department of Pathology and Cytology at Columbia University published a research paper titled Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons in the journal Cell stem cell . By analyzing the single-cell sequencing data of brain neurons in patients with frontotemporal dementia carrying the MAPT-N279K mutation, combined with pluripotent stem cell induction and cell transplantation, they found that brain neurons in patients with frontotemporal dementia carrying the MAPT-N279K mutation often have mitochondrial dysfunction, and that osteopontin (OPN) in neurons has an immunomodulatory effect and may be a potential therapeutic target.

MAPT-N279K is a common MAPT gene mutation that usually causes more 4R Tau to be generated and accumulate in neurons and glial cells in the forebrain and hindbrain. Patients carrying the MAPT-N279K mutation can observe early symptoms in the substantia nigra (SN) region of the brain as early as around 43 years old, and patients also have some Parkinson's-like behavioral disorders.

At the same time, the substantia nigra is also a common lesion area in all types of frontotemporal dementia, so the research team chose the substantia nigra as the research object (Figure 1). They found that the substantia nigra of patients is much smaller than that of normal people in terms of both area and number of neurons, and there are a large number of neural tangles and microglial proliferation.

Figure 1 Neuronal loss and microglial proliferation in the substantia nigra of patients with frontotemporal dementia

Through single-cell sequencing analysis of substantia nigra neurons in patients with frontotemporal dementia, the research team found that compared with normal people, the differentially expressed gene functions in the brains of patients with frontotemporal dementia are mainly concentrated in some functional pathways related to neurodegenerative diseases, as well as some inflammatory and oxidative phosphorylation functional pathways. To further explore the differences between patient neurons and normal neurons, the research team used human induced pluripotent stem cells (human iPSCs) to construct a MAPT-N279K mutant cell line and found that the mutated neurons had significantly improved basal respiration, ATP production capacity, and maximum respiration capacity compared to normal neurons, indicating that the MAPT-N279K mutation enhances the oxidative phosphorylation of neurons.

Combined with previous single-cell sequencing data, the research team also detected the up-regulated expression of inflammation-related genes C3, SPARC and SPP1 (i.e. osteopontin, OPN) in the MAPT-N279K mutant cell line. However, only OPN was regulated by reactive oxygen species (which can promote the occurrence of pro-inflammatory reactions), indicating that OPN is a downstream gene of reactive oxygen species regulating neuronal pro-inflammatory reactions. In addition, OPN, a pro-inflammatory factor, can cause an inflammatory response in microglia, resulting in up-regulated expression of related factors including TNF, MITF, GPNMB and CXCR4. At the same time, these phenomena were also observed after the research team transplanted the MAPT-N279K mutant cell line into mice, and inhibiting the expression of OPN can effectively alleviate the occurrence of these phenomena (Figure 2).

Figure 2 Osteopontin induces inflammation and neuronal death in neurons of patients with frontotemporal dementia with the MAPT-N279K gene mutation

The research team's results provide a potential therapeutic target for the treatment of frontotemporal dementia . However, there are still some issues that deserve further exploration by subsequent researchers. For example, the samples of this single-cell sequencing are limited to the substantia nigra of the patients' brains, while the pathological changes in the brains of patients with frontotemporal dementia often involve multiple brain regions. Therefore, the sequencing results of other brain regions are also worthy of further exploration in order to obtain more potential targets. The research team also suggested that although OPN may be a target for the treatment of frontotemporal dementia, frontotemporal dementia is a disease with a complex pathogenesis, and we do not necessarily regard OPN as the only target. We also hope that more research on frontotemporal dementia will appear in the future.

References:

[1] Al-Dalahmah O, Lam M, McInvale JJ, Qu W, Nguyen T, Mun JY, Kwon S, Ifediora N, Mahajan A, Humala N, Winters T, Angeles E, Jakubiak KA, Kühn R, Kim YA, De Rosa MC, Doege CA, Paryani F, Flowers X, Dovas A, Mela A, Lu H, DeTure MA, Vonsattel JP, Wszolek ZK, Dickson DW, Kuhlmann T, Zaehres H, Schöler HR, Sproul AA, Siegelin MD, De Jager PL, Goldman JE, Menon V, Canoll P, Hargus G. Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons. Cell Stem Cell. 2024 Apr 10:S1934-5909(24)00094-8. doi: 10.1016/j.stem.2024.03.013. Epub ahead of print. PMID: 38626772.