Increased Amoeboid Microglial Density in the Olfactory Bulb of Parkinson's and Alzheimer's Patients

Abstract

The olfactory bulb (OB) is affected early in both Parkinson's (PD) and Alzheimer's disease (AD), evidenced by the presence of disease-specific protein aggregates and an early loss of olfaction. Whereas previous studies showed amoeboid microglia in the classically affected brain regions of PD and AD patients, little was known about such changes in the OB. Using a morphometric approach, a significant increase in amoeboid microglia density within the anterior olfactory nucleus (AON) of AD and PD patients was observed. These amoeboid microglia cells were in close apposition to β-amyloid, hyperphosphorylated tau or α-synuclein deposits, but no uptake of pathological proteins by microglia could be visualized. Subsequent analysis showed (i) no correlation between microglia and α-synuclein (PD), (ii) a positive correlation with β-amyloid (AD), and (iii) a negative correlation with hyperphosphorylated tau (AD). Furthermore, despite the observed pathological alterations in neurite morphology, neuronal loss was not apparent in the AON of both patient groups. Thus, we hypothesize that, in contrast to the classically affected brain regions of AD and PD patients, within the AON rather than neuronal loss, the increased density in amoeboid microglial cells, possibly in combination with neurite pathology, may contribute to functional deficits.

Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

“…While general microgliosis has been repeatedly demonstrated in several pathological sites in PD, including the SN, HC and OB, little was known about the brain region-specific phenotypes of microglia and differences between presymptomatic and established PD [23,57,58]. In both the SN and HC of PD patients, the number of activated, CD68 positive, amoeboid microglial cells was increased.…”

“…Classification of ramified and amoeboid microglia morphology was performed as described in detail before [23]. Microglial cells were identified by positive CD68 immunoreactivity (IR) [53].…”

“…Both microglial subtypes are characterized by cytoplasmic staining, but the ramified microglial celltype can be distinguished by its small cell body and thin, radially projecting processes. Amoeboid microglia are characterized by a densely CD68-stained cell body typically surrounded by no or only very few short/stump processes [23]. Furthermore, we defined Iba1 positive ramified microglia as cells having a small circular body with highly ramified processes.…”

“…While in vitro and experimental animal studies had demonstrated that α-synuclein can trigger microglial activation, in vivo imaging and post-mortem immunohistochemical studies have now established the presence of amoeboid microglia and pro-inflammatory mediators in the substantia nigra (SN) in PD [11,16–20]. Interestingly, increased densities of amoeboid microglia were also observed in the olfactory bulb (OB) of PD patients and in a mouse model for PD (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [21,22,23,24]. Thus, microglial activation occurs also outside the SN, where it coincides with α-synuclein deposition.…”

Transolfactory neuroinvasion by viruses threatens the human brain

“…In humans, however, there is a scantiness of direct evidence demonstrating this route of CNS entry because of the restricted availability of human nervous tissues from the nasal epithelium to the olfactory bulb/tract. Detailed investigation of such human specimens will expand our understanding of the neuropathogenesis of virus-induced encephalitis/encephalopathy and some neurodegenerative disorders in which early olfactory dysfunction and olfactory bulb pathology have much been described, such as Alzheimer's and Parkinson's diseases (Doorn et al, 2014). Furthermore, early and prominent olfactory dysfunction and pathology are common in demyelinating disorders including multiple sclerosis (DeLuca et al, 2015).…”