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http://dx.doi.org/10.5483/BMBRep.2021.54.6.055

Olfactory neuropathology in Alzheimer's disease: a sign of ongoing neurodegeneration  

Son, Gowoon (Department of Brain & Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology (DGIST))
Jahanshahi, Ali (Department of Neurosurgery, MUMC+)
Yoo, Seung-Jun (Convergence Research Advanced Centre for Olfaction, DGIST)
Boonstra, Jackson T. (Department of Neurosurgery, MUMC+)
Hopkins, David A. (Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University)
Steinbusch, Harry W.M. (Department of Brain & Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology (DGIST))
Moon, Cheil (Department of Brain & Cognitive Sciences, Graduate School, Daegu Gyeungbuk Institute of Science and Technology (DGIST))
Publication Information
BMB Reports / v.54, no.6, 2021 , pp. 295-304 More about this Journal
Abstract
Olfactory neuropathology is a cause of olfactory loss in Alzheimer's disease (AD). Olfactory dysfunction is also associated with memory and cognitive dysfunction and is an incidental finding of AD dementia. Here we review neuropathological research on the olfactory system in AD, considering both structural and functional evidence. Experimental and clinical findings identify olfactory dysfunction as an early indicator of AD. In keeping with this, amyloid-β production and neuroinflammation are related to underlying causes of impaired olfaction. Notably, physiological features of the spatial map in the olfactory system suggest the evidence of ongoing neurodegeneration. Our aim in this review is to examine olfactory pathology findings essential to identifying mechanisms of olfactory dysfunction in the development of AD in hopes of supporting investigations leading towards revealing potential diagnostic methods and causes of early pathogenesis in the olfactory system.
Keywords
Alzheimer's disease; Olfactory bulb; Olfactory dysfunction; Olfactory epithelium; Olfactory sensory neuron; Pathophysiology;
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1 Gottfried JA (2010) Central mechanisms of odour object perception. Nat Rev Neurosci 11, 628-641   DOI
2 Ubeda-Banon I, Saiz-Sanchez D, Flores-Cuadrado A et al (2020) The human olfactory system in two proteinopathies: Alzheimer's and Parkinson's diseases. Transl Neurodegener 9, 22   DOI
3 Cao L, Schrank BR, Rodriguez S et al (2012) Abeta alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo. Nat Commun 3, 1009   DOI
4 Braak H and Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239-259   DOI
5 Pankratz VS, Roberts RO, Mielke MM et al (2015) Predicting the risk of mild cognitive impairment in the Mayo Clinic Study of Aging. Neurology 84, 1433-1442   DOI
6 Wilson RS, Arnold SE, Tang Y and Bennett DA (2006) Odor identification and decline in different cognitive domains in old age. Neuroepidemiology 26, 61-67   DOI
7 Solbu TT and Holen T (2012) Aquaporin pathways and mucin secretion of Bowman's glands might protect the olfactory mucosa. Chem Senses 37, 35-46   DOI
8 No authors listed (2021) 2021 Alzheimer's disease facts and figures. Alzheimers Dement 17, 327-406   DOI
9 Braubach OR, Miyasaka N, Koide T, Yoshihara Y, Croll RP and Fine A (2013) Experience-dependent versus experience-independent postembryonic development of distinct groups of zebrafish olfactory glomeruli. J Neurosci 33, 6905-6916   DOI
10 Thomann PA, Dos Santos V, Toro P, Schonknecht P, Essig M and Schroder J (2009) Reduced olfactory bulb and tract volume in early Alzheimer's disease--a MRI study. Neurobiol Aging 30, 838-841   DOI
11 Murphy C (2019) Olfactory and other sensory impairments in Alzheimer disease. Nat Rev Neurol 15, 11-24   DOI
12 Ownby RL, Crocco E, Acevedo A, John V and Loewenstein D (2006) Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 63, 530-538   DOI
13 Brzecka A, Leszek J, Ashraf GM et al (2018) Sleep disorders associated with Alzheimer's disease: a perspective. Front Neurosci 12, 330   DOI
14 Schubert CR, Carmichael LL, Murphy C, Klein BE, Klein R and Cruickshanks KJ (2008) Olfaction and the 5-year incidence of cognitive impairment in an epidemiological study of older adults. J Am Geriatr Soc 56, 1517-1521   DOI
15 Jack CR Jr, Wiste HJ, Therneau TM et al (2019) Associations of amyloid, tau, and neurodegeneration biomarker profiles with rates of memory decline among individuals without dementia. JAMA 321, 2316-2325   DOI
16 Wesson DW, Levy E, Nixon RA and Wilson DA (2010) Olfactory dysfunction correlates with amyloid-beta burden in an Alzheimer's disease mouse model. J Neurosci 30, 505-514   DOI
17 Firestein S (2001) How the olfactory system makes sense of scents. Nature 413, 211-218   DOI
18 Bathini P, Mottas A, Jaquet M, Brai E and Alberi L (2019) Progressive signaling changes in the olfactory nerve of patients with Alzheimer's disease. Neurobiol Aging 76, 80-95   DOI
19 Barwich AS (2020) Smellosophy: what the nose tells the mind. Harvard University Press ISBN: 9780674245426
20 Arnold SE, Lee EB, Moberg PJ et al (2010) Olfactory epithelium amyloid-beta and paired helical filament-tau pathology in Alzheimer disease. Ann Neurol 67, 462-469   DOI
21 Cao L, Rickenbacher GT, Rodriguez S, Moulia TW and Albers MW (2012) The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease. Sci Rep 2, 231   DOI
22 Yao ZG, Hua F, Zhang HZ, Li YY and Qin YJ (2017) Olfactory dysfunction in the APP/PS1 transgenic mouse model of Alzheimer's disease: morphological evaluations from the nose to the brain. Neuropathology 37, 485-494   DOI
23 Cheng N, Cai H and Belluscio L (2011) In vivo olfactory model of APP-induced neurodegeneration reveals a reversible cell-autonomous function. J Neurosci 31, 13699-13704   DOI
24 Kim JY, Rasheed A, Yoo SJ et al (2018) Distinct amyloid precursor protein processing machineries of the olfactory system. Biochem Biophys Res Commun 495, 533-538   DOI
25 Sakurai K, Shintani T, Jomura N, Matsuda T, Sumiyoshi A and Hisatsune T (2020) Hyper BOLD Activation in dorsal raphe nucleus of APP/PS1 Alzheimer's disease mouse during reward-oriented drinking test under thirsty conditions. Sci Rep 10, 3915   DOI
26 Wachowiak M and Cohen LB (2001) Representation of odorants by receptor neuron input to the mouse olfactory bulb. Neuron 32, 723-735   DOI
27 Dibattista M, Pifferi S, Menini A and Reisert J (2020) Alzheimer's disease: what can we learn from the peripheral olfactory system? Front Neurosci 14, 440   DOI
28 Thal DR, Rub U, Orantes M and Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791-1800   DOI
29 Murphy C, Bacon AW, Bondi MW and Salmon DP (1998) Apolipoprotein E status is associated with odor identification deficits in nondemented older persons. Ann N Y Acad Sci 855, 744-750   DOI
30 Heppner FL, Ransohoff RM and Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16, 358-372   DOI
31 DeTure MA and Dickson DW (2019) The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener 14, 32   DOI
32 Cummings J, Lee G, Ritter A, Sabbagh M and Zhong K (2020) Alzheimer's disease drug development pipeline: 2020. Alzheimers Dement (N Y) 6, e12050
33 Woodward MR, Dwyer MG, Bergsland N et al (2017) Olfactory identification deficit predicts white matter tract impairment in Alzheimer's disease. Psychiatry Res Neuroimaging 266, 90-95   DOI
34 Eerdunfu, Ihara N, Ligao B, Ikegaya Y and Takeuchi H (2017) Differential timing of neurogenesis underlies dorsalventral topographic projection of olfactory sensory neurons. Neural Dev 12, 2   DOI
35 Levai O, Breer H and Strotmann J (2003) Subzonal organization of olfactory sensory neurons projecting to distinct glomeruli within the mouse olfactory bulb. J Comp Neurol 458, 209-220   DOI
36 Khan A, Plana-Ripoll O, Antonsen S et al (2019) Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark. PLoS Biol 17, e3000353   DOI
37 Swan GE and Carmelli D (2002) Impaired olfaction predicts cognitive decline in nondemented older adults. Neuroepidemiology 21, 58-67   DOI
38 Miyamichi K, Serizawa S, Kimura HM and Sakano H (2005) Continuous and overlapping expression domains of odorant receptor genes in the olfactory epithelium determine the dorsal/ventral positioning of glomeruli in the olfactory bulb. J Neurosci 25, 3586-3592   DOI
39 Vyhnalek M, Magerova H, Andel R et al (2015) Olfactory identification in amnestic and non-amnestic mild cognitive impairment and its neuropsychological correlates. J Neurol Sci 349, 179-184   DOI
40 Woodward MR, Hafeez MU, Qi Q et al (2018) Odorant Item specific olfactory identification deficit may differentiate Alzheimer disease from aging. Am J Geriatr Psychiatry 26, 835-846   DOI
41 Liberia T, Martin-Lopez E, Meller SJ and Greer CA (2019) Sequential maturation of olfactory sensory neurons in the mature olfactory epithelium. eNeuro 6, ENEURO.0266-19. 2019
42 Storace DA and Cohen LB (2017) Measuring the olfactory bulb input-output transformation reveals a contribution to the perception of odorant concentration invariance. Nat Commun 8, 81   DOI
43 Brann JH, Ellis DP, Ku BS, Spinazzi EF and Firestein S (2015) Injury in aged animals robustly activates quiescent olfactory neural stem cells. Front Neurosci 9, 367   DOI
44 Burmeister HP, Bitter T, Heiler PM et al (2012) Imaging of lamination patterns of the adult human olfactory bulb and tract: in vitro comparison of standard- and high-resolution 3T MRI, and MR microscopy at 9.4 T. Neuroimage 60, 1662-1670   DOI
45 Cheng H, Saffari A, Sioutas C, Forman HJ, Morgan TE and Finch CE (2016) Nanoscale particulate matter from urban traffic rapidly induces oxidative stress and inflammation in olfactory epithelium with concomitant effects on brain. Environ Health Perspect 124, 1537-1546   DOI
46 Graziadei PP, Levine RR and Graziadei GA (1978) Regeneration of olfactory axons and synapse formation in the forebrain after bulbectomy in neonatal mice. Proc Natl Acad Sci U S A 75, 5230-5234   DOI
47 Login H, Haglin S, Berghard A and Bohm S (2015) The stimulus-dependent gradient of Cyp26B1+ olfactory sensory neurons is necessary for the functional integrity of the olfactory sensory map. J Neurosci 35, 13807-13818   DOI
48 Morrison EE and Costanzo RM (1990) Morphology of the human olfactory epithelium. J Comp Neurol 297, 1-13   DOI
49 Maresh A, Rodriguez Gil D, Whitman MC and Greer CA (2008) Principles of glomerular organization in the human olfactory bulb--implications for odor processing. PLoS One 3, e2640   DOI
50 Hasegawa-Ishii S, Shimada A and Imamura F (2017) Lipopolysaccharide-initiated persistent rhinitis causes gliosis and synaptic loss in the olfactory bulb. Sci Rep 7, 11605   DOI
51 Devanand DP, Liu X, Tabert MH et al (2008) Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease. Biol Psychiatry 64, 871-879   DOI
52 Coleman JH, Lin B, Louie JD, Peterson J, Lane RP and Schwob JE (2019) Spatial determination of neuronal diversification in the olfactory epithelium. J Neurosci 39, 814-832   DOI
53 Son G, Yoo SJ, Kang S et al (2021) Region-specific amyloid-beta accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice. Alzheimers Res Ther 13, 4   DOI
54 Oka Y, Takai Y and Touhara K (2009) Nasal airflow rate affects the sensitivity and pattern of glomerular odorant responses in the mouse olfactory bulb. J Neurosci 29, 12070-12078   DOI
55 Zapiec B, Dieriks BV, Tan S, Faull RLM, Mombaerts P and Curtis MA (2017) A ventral glomerular deficit in Parkinson's disease revealed by whole olfactory bulb reconstruction. Brain 140, 2722-2736   DOI
56 Stamps JJ, Bartoshuk LM and Heilman KM (2013) A brief olfactory test for Alzheimer's disease. J Neurol Sci 333, 19-24   DOI
57 Cheng N, Jiao S, Gumaste A, Bai L and Belluscio L (2016) APP overexpression causes abeta-independent neuronal death through intrinsic apoptosis pathway. eNeuro 3, ENEURO.0150-16.2016
58 Bonzano S, Bovetti S, Gendusa C, Peretto P and De Marchis S (2016) Adult born olfactory bulb dopaminergic interneurons: molecular determinants and experience-dependent plasticity. Front Neurosci 10, 189   DOI
59 Ramachandran VS (2002) Encyclopedia of the human brain, Academic Press, San Diego, Calif.
60 Sahay A, Wilson DA and Hen R (2011) Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582-588   DOI
61 Holbrook EH and Coelho DH (2020) Cranial nerve stimulation for olfaction (cranial nerve 1). Otolaryngol Clin North Am 53, 73-85   DOI
62 Kim YH, Lee SM, Cho S et al (2019) Amyloid beta in nasal secretions may be a potential biomarker of Alzheimer's disease. Sci Rep 9, 4966   DOI
63 Doty RL, Shaman P and Dann M (1984) Development of the University of Pennsylvania smell identification test: a standardized microencapsulated test of olfactory function. Physiol Behav 32, 489-502   DOI
64 Calderon-Garciduenas L, Maronpot RR, Torres-Jardon R et al (2003) DNA damage in nasal and brain tissues of canines exposed to air pollutants is associated with evidence of chronic brain inflammation and neurodegeneration. Toxicol Pathol 31, 524-538   DOI
65 Zhao K, Dalton P, Yang GC and Scherer PW (2006) Numerical modeling of turbulent and laminar airflow and odorant transport during sniffing in the human and rat nose. Chem Senses 31, 107-118   DOI
66 Imai T, Sakano H and Vosshall LB (2010) Topographic mapping--the olfactory system. Cold Spring Harb Perspect Biol 2, a001776   DOI
67 Tabert MH, Liu X, Doty RL et al (2005) A 10-item smell identification scale related to risk for Alzheimer's disease. Ann Neurol 58, 155-160   DOI
68 Yoo SJ, Son G, Bae J et al (2020) Longitudinal profiling of oligomeric Aβ in human nasal discharge reflecting cognitive decline in probable Alzheimer's disease. Sci Rep 10, 11234   DOI
69 Yoo SJ, Lee JH, Kim SY et al (2017) Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of beta-amyloid oligomer. Cell Death Dis 8, e2977   DOI
70 Saiz-Sanchez D, De la Rosa-Prieto C, Ubeda-Banon I and Martinez-Marcos A (2015) Interneurons, tau and amyloidbeta in the piriform cortex in Alzheimer's disease. Brain Struct Funct 220, 2011-2025   DOI
71 Imamura F and Hasegawa-Ishii S (2016) Environmental toxicants-induced immune responses in the olfactory mucosa. Front Immunol 7, 475   DOI
72 Bozek A, Bednarski P and Jarzab J (2016) Allergic rhinitis, bronchial asthma and other allergies in patients with Alzheimer's disease: unnoticed issue. Postepy Dermatol Alergol 33, 353-358
73 Steinfeld R, Herb JT, Sprengel R, Schaefer AT and Fukunaga I (2015) Divergent innervation of the olfactory bulb by distinct raphe nuclei. J Comp Neurol 523, 805-813   DOI
74 He B, Zheng M, Liu Q et al (2018) Injected amyloid beta in the olfactory bulb transfers to other brain regions via neural connections in mice. Mol Neurobiol 55, 1703-1713   DOI
75 Roberts RO, Christianson TJ, Kremers WK et al (2016) Association between olfactory dysfunction and amnestic mild cognitive impairment and Alzheimer disease dementia. JAMA Neurol 73, 93-101   DOI
76 Vasavada MM, Martinez B, Wang J et al (2017) Central olfactory dysfunction in Alzheimer's disease and mild cognitive impairment: a functional MRI study. J Alzheimers Dis 59, 359-368   DOI
77 Michelsen KA, Prickaerts J and Steinbusch HW (2008) The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer's disease. Prog Brain Res 172, 233-264   DOI
78 Rey NL, Wesson DW and Brundin P (2018) The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol Dis 109, 226-248   DOI