Enhanced expression of autophagy‐related p62 without increased deposits of neurodegeneration‐associated proteins in glioblastoma and surrounding tissue – An autopsy‐based study

Abstract

Neurodegenerative diseases are a major health burden. The underlying causes are not yet fully understood, but different mechanisms such as cell stress and chronic inflammation have been described as contributing factors. Neurodegenerative changes have been observed in the vicinity of brain tumors, typically around slowly growing benign lesions. Moreover, in‐vitro data suggest a potential induction of pathological tau deposits also in glioblastoma, a highly malignant and proliferative brain cancer. The aim of this study was to evaluate neurodegeneration‐associated protein deposition and autophagy as well as microglial activation within and surrounding glioblastoma. Post‐mortem brain tissue of 22 patients with glioblastoma was evaluated immunohistochemically for phosphorylated tau, beta‐amyloid, alpha‐synuclein and phosphorylated TDP‐43. Additionally, the autophagy marker p62 and the microglial marker HLA‐DR were investigated. The data was compared to 22 control cases and ten cases with other space occupying brain lesions. An increase of p62‐immunoreactivity was observed within and adjacent to the glioblastoma tumor tissue. Moreover, dense microglial infiltration in the tumor tissue and the immediate surrounding brain tissue was a constant feature. Deposition of neurodegeneration‐associated proteins was found in the majority of cases (86.4%) but in distant sites. These findings suggested a preexisting neurodegenerative pathology, which followed a typical distributional pattern: ten cases with Alzheimer disease neuropathological changes, including two severe cases, eight cases with primary age‐related tauopathy, six cases with aging‐related tau astrogliopathy and one case with progressive supranuclear palsy. Collectively, our data suggests enhanced autophagy in glioblastoma tumor cells and the surrounding brain. The variety and distribution of distant neurodegeneration‐associated protein aggregates observed in the majority of cases, suggest a preexisting rather than a tumor‐induced neurodegenerative condition.

Coexisting Biopsy-Diagnosed Dementia and Glioblastoma

“…This study suggested a direct link between AD and GBM or that GBM might promote neurodegeneration rather than oppose it [15]. Another study posited that neurodegeneration occurs before tumor formation, given that post-mortem GBM samples showed neurodegenerative-associated proteins, such as Aβ and tau, present in the majority of cases but in distant sites and in an age-expected amount and distribution compared to controls [3].…”

“…Both glioblastoma (GBM) and dementia are devastating diseases with limited treatments that are usually not curative [1]. Having clinically diagnosed dementia with an associated biopsy-proven etiology and a coexisting GBM diagnosis is a rare occurrence [2,3]. The relationship between the development of neurodegenerative dementia and GBM is unclear [3].…”

“…Having clinically diagnosed dementia with an associated biopsy-proven etiology and a coexisting GBM diagnosis is a rare occurrence [2,3]. The relationship between the development of neurodegenerative dementia and GBM is unclear [3]. Some studies have observed an inverse correlation between cancer and neurodegenerative disease incidence, with cancer peaking around age 60 years, but beyond that, neurodegenerative diseases increase in the elderly [4].…”

“…Lehrer postulated a potential mechanistic relationship between AD and GBM given that AD prevalence and GBM incidence paralleled in some US states [6]. Certain similarities between dementia and GBM suggest a direct association, including neurodegeneration-associated protein deposits, inflammation, and intestinal microbiota alterations [1,3].…”

“…AD is the most common neurodegenerative disease [3]. Though the exact mechanism of injury is unknown, accumulation of abnormally folded amyloid-β (Aβ) plaques and hyper-phosphorylated tau neurofibrillary tangles with the presence of cerebral amyloid angiopathy (CAA) are present [6,7].…”