Pathological mitochondria in neurons and perivascular astrocytic endfeet of idiopathic normal pressure hydrocephalus patients

Per Kristian Eide,Rune Enger,Hans-Arne Hansson,Erlend A Nagelhus,Md Mahdi Hasan-Olive

doi:10.1186/s12987-019-0160-7

Per Kristian Eide, Rune Enger + Show 3 more

Open Access

https://doi.org/10.1186/s12987-019-0160-7

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Abstract

BackgroundA growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes.MethodsCortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels.ResultsWe found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry.ConclusionOur results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer’s disease.

Highlights

A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus is associated with delayed extravascular clearance of metabolic waste
Biopsies from the 30 idiopathic normal pressure hydrocephalus (iNPH) patients were from grey matter of frontal cortex, while REF biospies were from the grey matter of temporal cortex in four epilepsy cases, frontal cortex in three patients (2 aneurysm, 1 tumor), parieto-occipital cortex in one epilepsy case, and the occipital cortex in another epilepsy patient
Normal and pathological mitochondria in neurons Neuronal soma From each individual of the REF and iNPH cohorts, we examined on average 12.7 ± 6.5 and 12.1 ± 5.8 soma, which included a mean cytoplasmic area of 16,982,978 ± 5,335,206 nm2 and 21,797,964 ± 7,383,110 nm2, respectively

Summary

Introduction

A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated with delayed extravascular clearance of metabolic waste. A significant proportion of iNPH patients presents with extra-cellular accumulation of amyloid-β, and intracellular accumulation of hyperphosphorylated tau (HPτ) [5,6,7]. Both are hallmarks of Alzheimer’s disease, related to defective clearance of the brain metabolites. Evidence suggests that glymphatic function may become impaired with increasing age [13], and in Alzheimer’s disease [9]. With regard to iNPH, recent imaging studies have provided evidence for delayed glymphatic clearance of molecules from the extravascular space of the entire brain [14,15,16]

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