Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer\u2019s disease and aged brains: increased levels correlate with neuropathology

Anarmaa Mendsaikhan,Thomas G Beach,Lucia I Sue,Lih-Fen Lue,Geidy E Serrano,Douglas G Walker,Jean-Pierre Bellier,Ikuo Tooyama

doi:10.1186/s40478-019-0862-8

Abstract

Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer’s disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.

Highlights

Alzheimer’s disease (AD) is the most frequent cause of dementia in elderly populations and currently affecting an estimated 47 million people worldwide [1], but as the ages of populations in most countries are increasing, the incidence of AD will significantly increase
While most experimental studies on PGRN in brain have employed animal models of frontotemporal dementia (FTD) with single mutation or GRN gene knockout, the number of studies relating to PGRN and AD are limited, but one feature observed in studies of AD transgenic mice and human brain samples was that PGRN accumulated around Aβ plaques [19, 31,32,33,34]
We identified that PGRN and PSAP expression were increased in AD cases, and their interaction could be demonstrated in human brain samples

Summary

Introduction

Alzheimer’s disease (AD) is the most frequent cause of dementia in elderly populations and currently affecting an estimated 47 million people worldwide [1], but as the ages of populations in most countries are increasing, the incidence of AD will significantly increase. In FTD, loss of function mutations in the GRN gene resulting in significantly reduced levels of PGRN protein lead to neurodegeneration [15]. Increasing PGRN levels in animal models of FTD, AD and Parkinson’s disease (PD) have been reported to reduce both pathological and clinical features [19, 23, 25,26,27]. While most experimental studies on PGRN in brain have employed animal models of FTD with single mutation or GRN gene knockout, the number of studies relating to PGRN and AD are limited, but one feature observed in studies of AD transgenic mice and human brain samples was that PGRN accumulated around Aβ plaques [19, 31,32,33,34]. An additional study that employed granulin domain-specific antibodies showed immunoreactivity of neurons, microglia and structures associated with plaques [35]

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