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

• Published in: Fluids and barriers of the CNS 2019-12, Vol.16 (1), p.39-39, Article 39
• Main Authors: Hasan-Olive, Md Mahdi, Enger, Rune, Hansson, Hans-Arne, Nagelhus, Erlend A, Eide, Per Kristian
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; alzheimers-disease; Amyloid; Aquaporin 4; Aquaporins; Astrocytes; Astrocytes - pathology; Astrocytes - ultrastructure; Autophagic vacuoles; Autophagy; biogenesis; Biopsy; Brain - pathology; Brain - ultrastructure; Brain research; Clinical Medicine; Cortex; defective axonal-transport; degradation; Dementia; Dementia disorders; Electron microscopy; Endoplasmic reticulum; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum - ultrastructure; Ethics; Gliosis; Glymphatic System - pathology; Glymphatic System - ultrastructure; Humans; Hydrocephalus; Hydrocephalus, Normal Pressure - pathology; Idiopathic normal; Immunogold electron microscopy; Immunohistochemistry; impairment; Klinisk medicin; Light microscopy; management; Metabolites; Microscopy; Mitochondria; Mitochondria - pathology; Mitochondria - ultrastructure; Mitophagy; Nerve endings; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - pathology; Neurons - ultrastructure; Neurosciences & Neurology; Neurosurgery; NMR; Normal pressure hydrocephalus; Nuclear magnetic resonance; Patients; Phenotypes; Pressure; pressure hydrocephalus; proteins; Sensors; Surgery; Synapses - pathology; Synapses - ultrastructure; synaptic degeneration; Tau protein; Transmission electron microscopy; Urinary incontinence; Vacuoles
• ISSN: 2045-8118; 2045-8118
• DOI: 10.1186/s12987-019-0160-7

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. 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. Cortical 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. We 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. Our 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.