Reduction in TOM1 expression exacerbates Alzheimer’s disease

Recently, Martini et al. (1) compared human Alzheimer’s disease (AD) hippocampi and an AD mouse model with respective controls and found that TOM1 steady-state levels in the AD group are reduced. Therefore, five conclusions have been obtained: 1) Impairment in TOM1 levels causes IL-1R1 overexpression in AD. 2) Knockdown of TOM1 exacerbates immune response. 3) Reduced TOM1 impairs microglial phagocytic efficiency. 4) The amyloid-beta (Aβ) deposition is enhanced by the reduction in TOM1. 5) Loss of TOM1 causes the exacerbation of cognitive decline. We deeply agree with Martini et al.’s (1) views on the function of TOM1. However, since TOM1 can help reduce Aβ deposition, we infer that the expression of TOM1 in patients with AD at least in the early stages of AD should increase. To verify our assumption, a single-cell dataset is used to test TOM1 expression in patients in different stages of AD compared with controls.

The single-cell dataset we used is from Mathys et al.’s (2) study. They analyzed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer’s disease pathology. We summarize their data in Table 1. Excitatory neurons (EX) and microglia (Mic) are selected to compare the different expression of TOM1 in different subgroups. In Table 1, IndModel.adj.pvals means false discovery rate-adjusted P values (two-sided Wilcoxon rank-sum test), IndModel.FC means log2 fold change of one group mean value relative to that of the other group. They divided the 48 individuals into four groups: no pathology, early pathology, pathology, and late pathology.

Table 1.

TOM1 expression in different cell types and different subgroups

Cell type	IndModel.adj.pval	No.pathology.mean	Pathology.mean	Early.pathology.mean	Late.pathology.mean	IndModel.FC
EX	1.01E-07			0.100377	0.094453	−0.08776
	6.14E-23	0.128393		0.146853		0.193803
	3.00E-17	0.128926	0.144562			0.165147
Mic	0.899084			0.044636	0.034652	−0.36527
	0.979583	0.035452		0.042146	0.034652	0.249503
	0.854449	0.035924	0.038419			0.096888

In Table 1, we can clearly see that the expression of TOM1 in no pathology is lower than that in early pathology and pathology in both excitatory neurons and microglia, which is not consistent with the conclusion of Martini et al. (1). Although the difference in Mic is not significant due to the sample size, the mean expression of TOM1 in early pathology and pathology is still higher than in no pathology. However, compared with the early-pathology group, the expression of TOM1 in excitatory neurons is significantly reduced in late pathology. A similar downward trend is also manifested in microglia cells. This interesting phenomenon confirms our conjecture to some extent. Since TOM1 can help reduce Aβ deposition, we believe TOM1’s function is activated due to the increasing Aβ deposition, which causes the high expression of TOM1 in the early-pathology and pathology groups. However, with the weakening of TOM1 expression, early-pathology and pathology patients were transformed into late-pathology patients due to the deposition of Aβ.

Overall, the expression of TOM1 would be increased in patients with early AD and AD. A decrease in TOM1 expression would result in aggravation of patients with early AD and AD to patients with late AD.