FTLD-TDP With and Without GRN Mutations Cause Different Patterns of CA1 Pathology

Abstract

Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A). PGRN is a highly conserved, secreted glycoprotein and functions in the central nervous system as a key modulator of microglial function. Hence, altered microglial function caused by PGRN deficiency may be tied to the pathogenesis of FTLD-TDP. Our previous studies showed that haploinsufficiency of GRN mutations extends to microglial PGRN expression in the hippocampal CA1 region. In this study, we found that the CA1 sector was associated with less neuronal loss and more frequent TDP-43 inclusions in FTLD-TDP type A cases with GRN mutations than in sporadic cases. In addition, the CA1 region in GRN mutation cases contained more rod-like microglia, which also had reduced PGRN expression. These findings suggest that the profile of TDP-43 inclusions, neuronal number, and microgliosis in the CA1 sector of FTLD-TDP type A cases may be influenced by GRN gene expression status.

Keywords: Frontotemporal lobar degeneration; Hippocampal sclerosis; Microglia; Neuroinflammation; Progranulin; TAR DNA-binding protein 43.

FIGURE 1.

Illustrations of none (A), sparse (B), moderate (C), and frequent (D) IBA-1-positive rod-like microglia. In this paper, we specifically defined a rod-shaped microglial cell as 1 having a cell length equal to or more than 40 µm. Arrow, rod-shaped microglial cell. Bar: 50 µm.

FIGURE 2.

Hematoxylin and eosin stains reveal unsynchronized neuronal loss in the CA1 region and subiculum of brains with GRN mutations. Neuronal loss is mostly mild in the CA1 region (A), severe in the subiculum (B), and minimal in the CA3 region (C) of FTLD-TDP type A with GRN mutation (GRN+/−) brains. However, neuronal loss is severe in both the CA1 region (D) and subiculum (E), and minimal in the CA3 region (F) of FTLD-TDP type A without GRN mutation brains (FTLD-TDP type A). Bar: 50 µm.

FIGURE 3.

IBA-1-positive microglia in the hippocampi of brains with different diseases. Sparse IBA-1-positive, rod-shaped microglia are present in the CA1 region in normal controls (CON, A), in Alzheimer disease (AD, B), in AD with hippocampal sclerosis (ADHS, C), and in FTLD-TDP type A without GRN mutations (FTLD-TDP type A, D), and are frequent in FTLD-TDP type A with GRN mutations (GRN, E and F). The rod-like microglia in FTLD-TDP type A with GRN mutations form end-to-end alignments (F). Bar: 50 µm.

FIGURE 4.

PGRN-positive microglia in the hippocampi of brains with different diseases. Sparse PGRN-positive microglia are present in the CA1 region in normal controls (CON, A) and in FTLD-TDP type A with GRN mutations (GRN+/−, B). Frequent PGRN-positive microglia are found in the CA1 region in Alzheimer disease with hippocampal sclerosis (ADHS, C) and FTLD-TDP type A without GRN mutations (FTLD-TDP type A, D). Bar: 50 µm.

FIGURE 5.

Frequent TDP-43 dystrophic neurites (DNs) in the CA1 region of the brain with FTLD-TDP type A with GRN mutations (A, B). Sparse TDP-43 DNs in the CA1 region of the brain with FTLD-TDP type A without GRN mutations (C). Bar in A, 500 µm; bar in C, 20 µm for B and C.