Huntingtin Aggregates in the Olfactory Bulb in Huntington’s Disease

Abstract

Olfactory deficits are an early and prevalent non-motor symptom of Huntington's disease (HD). In other neurodegenerative diseases where olfactory deficits occur, such as Alzheimer's disease and Parkinson's disease, pathological protein aggregates (tau, β-amyloid, α-synuclein) accumulate in the anterior olfactory nucleus (AON) of the olfactory bulb (OFB). Therefore, in this study we determined whether aggregates are also present in HD OFBs; 13 HD and five normal human OFBs were stained for mutant huntingtin (mHtt), tau, β-amyloid, TDP-43, and α-synuclein. Our results show that mHtt aggregates detected with 1F8 antibody are present within all HD OFBs, and mHtt aggregate load in the OFB does not correlate with Vonsattel grading scores. The majority of the aggregates were located in the AON and in similar abundance in each anatomical segment of the AON. No mHtt aggregates were found in controls; 31% of HD cases also contained tau neurofibrillary tangles within the AON. This work demonstrates HD pathology in the OFB and indicates that disease-specific protein aggregation in the AON is a common feature of neurodegenerative diseases that show olfactory deficits.

Lamina-specific immunohistochemical signatures in the olfactory bulb of healthy, Alzheimer’s and Parkinson’s disease patients

“…This agrees with previous studies that have described the laminar distribution of these neuronal markers using single immunoperoxidase labelling or triple immunofluorescence 17 , 20 – 28 . We observed calbindin labelled large neurons in the mitral cell layer and AON, which agrees with previous reports 18 , 21 . The distribution of glial markers such as Iba1 and GFAP has also been demonstrated previously 29 – 31 , as have a range of markers that label glomeruli, including OMP, VGLUT2, NCAM, PGP9.5, synaptophysin and UEA-I lectin 11 – 13 , 24 , 27 , 28 , 32 .…”

“…Histological staining or chromogenic labelling is commonly used to delineate subregions within the human olfactory bulb; however, the heterogenous laminar structure and inter-individual variability in structure makes any such delineation highly subjective. In particular, delineation of the anterior olfactory nucleus (AON) is important for studies of neurodegeneration as pathological aggregates such as α-synuclein, tau, β-amyloid, huntingtin and TAR DNA-binding protein 43 (TDP43) specifically accumulate in this region of the olfactory bulb in many neurodegenerative diseases 12 , 14 – 18 . To facilitate more accurate layer delineation, we used the MP-IHC approach to generate a comprehensive neurochemical atlas of the human bulb that identifies key structures, layers and cell populations.…”

Extending the Spectrum of Nonmotor Symptoms with Olfaction in Premotor Huntington’s Disease: A Pilot Study

“…There are few studies reporting olfactory dysfunction in manifest HD patients [2,3], supported by a recent neuropathological study establishing mHtt in the olfactory bulb of HD patients [6]. Furthermore, there are preceding studies assessing olfaction in premanifest HD mutation carriers by using the UPSIT, which did not show significant impairment in HD carriers, whereas manifest HD patients showed impaired odor identification progressive with disease course [4,5,17].…”

“…There are several studies reporting olfactory dysfunction in manifest HD patients [2,3] and some studies in premanifest HD carriers [4,5] which did 208 DOI: 10.1159/000518136 not show significant impairment in olfaction of mutation carriers using the University of Pennsylvania Smell Identification Test (UPSIT). Furthermore, a recent neuropathological study demonstrated HD-specific protein aggregation in the anterior olfactory nucleus which is common in HD [6].…”

Olfactory Dysfunction in Huntington’s Disease

“…Interestingly, these aggregates were not correlated with the Vonsattel grading system of neuropathology in HD, which focuses primarily on basal ganglia pathology, and no gradient was found along the olfactory bulb and tract, suggesting either the absence of aggregate progression or that deposition occurs earlier, and tissues are saturated in the later stages of disease. Demonstrating the specificity of protein aggregation, no α-synuclein, Lewy bodies, amyloid-β plaques (except for one patient), or phospho-TDP-43 were present in the anterior olfactory nucleus (AON) in these samples [ 66 ]. Despite such exciting progress, no studies explicitly correlating the concentration of mHtt protein deposits with olfactory status using a formal smell evaluation have been conducted.…”