Aberrant GAP43 Gene Expression Is Alzheimer Disease Pathology-Specific

We read with interest the study by Lan et al.¹ reporting the relation of presynaptic dysfunction with Alzheimer disease (AD) pathology. The authors found significantly higher cerebrospinal fluid (CSF) growth-associated protein-43 (GAP43) protein levels in A+/T+ compared to A−/T− or A+/T− and an association of CSF GAP43 with CSF tau levels independent of amyloid positivity and clinical diagnosis. Upstream of GAP43 protein synthesis, we investigated the association of GAP43 gene expression levels with AD pathology. We used brain bulk RNA-Seq and cell-type specific (CTS) gene expression data from the Religious Orders Study and Rush Memory and Aging Project (N = 583).

Association analyses of GAP43 gene expression levels with A/T groups (A−/T−, A+/T−, and A+/T+) in brain bulk tissue and CTS expression were performed, adjusting for age, sex, and APOE ε4 status. CTS expression levels were estimated from bulk RNA-Seq data using a Bayesian model bMIND.² Amyloidopathy and tauopathy were dichotomized neuropathologically by the Consortium to Establish a Registry for Alzheimer’s Disease scores³ and Braak staging,⁴ respectively. Amyloid positivity (A+) was defined as definite or probable AD, and amyloid negativity (A−) as possible AD or normal brain. Tau positivity (T+) was defined as Braak stage ≥ 4 and tau negativity (T−) as Braak stage ≤ 3.

Compared to A−/T−, GAP43 expression levels were significantly lower in A+/T+ (odds ratio [OR] = 0.69, p = 4.69 × 10⁻⁴; Figure A). Compared to A−/T−, GAP43 expression levels were marginally lower in A+/T− (OR = 0.81, p = 9.81 × 10⁻²).

FIGURE:

GAP43 gene expression levels in bulk brain tissue and cell-type specific gene expression. A−/T− (n = 181) is a group with negative amyloidopathy and negative tauopathy, A+/T− (n = 106) is a group with positive amyloidopathy but negative tauopathy, and A+/T+ (n = 296) is a group with positive amyloidopathy and positive tauopathy. The boxplots describe the median (horizontal bar), interquartile range (IQR; hinges), and 1.5 × IQR (whiskers). Each point represents a separate individual. The dashed horizontal line in A represents the median value of the A−/T− group. *p < 0.05, ***p < 0.001.

On cell-type levels, GAP43 expression levels were lower in astrocytes (OR = 0.87, false discovery rate [FDR]-corrected p = 1.20 × 10⁻²), microglia (OR = 0.89, FDR-corrected p= 1.35 × 10⁻²), and oligodendrocytes (OR = 0.80, FDR-corrected p = 1.20 × 10⁻²) in A+/T+ compared to A−/T−, but not in excitatory (OR = 1.03, FDR-corrected p = 3.28 × 10⁻¹) and inhibitory neurons (OR = 1.02, FDR-corrected p= 7.62 × 10⁻²; see Figure B).

In conclusion, we found lower expression levels of GAP43 in A+/T+ compared to A−/T− and no significant difference between A+/T− and A−/T− in brain bulk tissue. The significant difference in GAP43 expression corresponding to AD pathology is consistent with the results of the study by Lan et al. In CTS analyses, lower GAP43 expression levels in glial cells of A+/T+, but not in neurons, may indicate that the GAP43-related synaptic pathway in AD could involve glial cells rather than neurons. It is known that GAP43 expression levels increase in conjunction with axonal plasticity, memory processes, and following axonal injury.⁵ Future studies are needed to investigate the relationship between decreased cortical GAP43 gene expression and increased CSF GAP43 protein expression in AD.