Alzheimer's disease pathology in Nasu-Hakola disease brains

Abstract

Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either triggering receptor expressed on myeloid cells 2 (TREM2) or TYRO protein tyrosine kinase binding protein (TYROBP), alternatively named DNAX-activation protein 12 (DAP12), both of which are expressed on microglia in the brain and form the receptor-adaptor complex that chiefly recognizes anionic lipids. TREM2 transmits the signals involved in microglial survival, proliferation, chemotaxis, and phagocytosis. A recent study indicated that a loss of TREM2 function causes greater amounts of amyloid-β (Aβ) deposition in the hippocampus of a mouse model of Alzheimer's disease (AD) owing to a dysfunctional response of microglia to amyloid plaques, suggesting that TREM2 facilitates Aβ clearance by microglia. TREM2/DAP12-mediated microglial response limits diffusion and toxicity of amyloid plaques by forming a protective barrier. However, the levels of Aβ deposition in postmortem brains of NHD, where the biological function of the TREM2/DAP12 signaling pathway is completely lost, remain to be investigated. By immunohistochemistry, we studied the expression of Aβ and phosphorylated tau (p-tau) in the frontal cortex and the hippocampus of five NHD cases. Although we identified several small Aβ-immunoreactive spheroids, amyloid plaques were almost undetectable in NHD brains. We found a small number of p-tau-immunoreactive neurofibrillary tangle (NFT)-bearing neurons in NHD brains. Because AD pathology is less evident in NHD than the full-brown AD, it does not play an active role in the development of NHD.

Keywords: Alzheimer's disease; Nasu-Hakola disease; amyloid-β; phosphorylated tau.

Figure 1.

Aβ immunoreactivity in NHD and AD brains. (a) the hippocampus white matter of NHD (NHD4), Aβ (red) and Iba1 (brown), spheroids (arrows), (b) the frontal lobe white matter of NHD (NHD5), Aβ (red) and Iba1 (brown), spheroid, (c) the hippocampus white matter of NHD (NHD2), Aβ (red) and Iba1 (brown), spheroid, and (d) the frontal cortex of AD (AD8), Aβ (red) and Iba1 (brown), amyloid plaques.

Figure 2.

P-tau immunoreactivity in NHD and AD brains. (a) the hippocampus of NHD (NHD5), p-tau (red) and Iba1 (brown), no NFT, (b) the hippocampus of NHD (NHD1), p-tau (red) and Iba1 (brown), several NFTs, (c) the hippocampus of NHD (NHD2), p-tau (red) and Iba1 (brown), one NFT, and (d) the hippocampus of AD (AD5), p-tau (red) and Iba1 (brown), numerous NFTs.