Increased expression of the neuroplastin 65 protein is involved in neurofibrillary tangles and amyloid beta plaques in Alzheimer’s disease

Abstract

BACKGROUND

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions. Pathological hallmarks of AD include intracellular neurofibrillary tangles (NFTs) and extracellular amyloid beta (Aβ) plaques. Neuroplastin 65 (NP65), highly expressed in the brain, has been previously shown to mitigate cognitive impairments and decrease Aβ plaques in the AD mouse model, suggesting that NP65 is involved in AD neuropathology. However, direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.

AIM

To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.

METHODS

Immunohistochemical, immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains (AD = 10, controls = 9). Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau (AT-8, a marker for NFT) markers was performed to assess NP65 colocalization with Aβ plaques and NFTs.

RESULTS

In controls, NP65 was highly expressed in a wide-range of brain areas. AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions, including the frontal and temporal cortex, hippocampus, and cerebellum, compared to controls. Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls. Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβ plaques in AD brain tissue.

CONCLUSION

Our findings demonstrate a significant increase of NP65 protein, which colocalizes with NFTs and Aβ plaques in AD brains, providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.

Keywords: Neuroplastin 65 protein; Alzheimer’s disease; Neurofibrillary tangles; Amyloid beta; Hippocampus

Core Tip: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with pathological hallmarks including intracellular neurofibrillary tangles and extracellular amyloid beta (Aβ) plaques. Synaptic membrane glycoprotein neuroplastin 65 (NP65) has been previously shown to mitigate cognitive impairments and decrease Aβ plaques in the AD mouse model. However, direct evidence linking NP65 expression to AD pathology in human brain remains absent. The present study shows that NP65 is highly expressed in a wide-range of brain areas and is significantly increased in AD cases. In addition, we found colocalization of NP65 with neurofibrillary tangles and Aβ plaques in AD brain. Thus, this study provides direct evidence of NP65 involvement in AD pathology.