Olfactory dysfunction is a common symptom associated with neurodegenerative diseases including Alzheimer’s disease (AD). Although evidence exists to suggest that peripheral olfactory organs are involved in the olfactory dysfunction that accompanies AD pathology, the underlying mechanisms are not fully understood. As confirmed using behavioral tests, transgenic mice overexpressing a Swedish mutant form of human amyloid precursor proteins exhibited olfactory impairments prior to evidence of cognitive impairment. By measuring the expression of tyrosine hydroxylase, we observed that specific regions of the olfactory bulb (OB) in Tg2576 mice, specifically the ventral portion exhibited significant decreases in the number of dopaminergic neurons in the periglomerular regions from the early stage of AD. To confirm the direct linkage between these olfactory impairments and AD-related pathology, β-site amyloid precursor protein cleaving enzyme 1 (BACE1)—the initiating enzyme in Aβ genesis—and β-amyloid peptide (Aβ), hallmarks of AD were analyzed. We found that an increase in BACE1 expression coincided with an elevation of amyloid-β (Aβ) oligomers in the ventral region of OB. Moreover, olfactory epithelium (OE), in particular the ectoturbinate in which axons of olfactory sensory neurons (OSNs) have direct connections with the dendrites of mitral/tufted cells in the ventral part of OB, exhibited significant decreases in both thickness and cell number even at early stages. This result suggests that Aβ oligomer toxicity in the OE may have induced a decline in the number of OSNs and functional impairment of the olfactory system. We first demonstrated that disproportionate levels of regional damage in the peripheral olfactory system may be a specific symptom of AD with Aβ oligomer accumulation occurring prior to damage within the CNS. This regional damage in the olfactory system early in the progression of AD may be closely related to AD-related pathological abnormality and olfactory dysfunction found in AD patients.

Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Therefore, the development of EPO analogs that would confer neuroprotection without adverse effects has been attempted. In this study, we examined the potential of a novel EPO-based short peptide, MK-X, as a novel drug for stroke treatment in comparison with EPO. We found that MK-X administration with reperfusion dramatically reduced brain injury in an in vivo mouse model of ischemic stroke induced by middle cerebral artery occlusion, whereas EPO had little effect. Similar to EPO, MK-X efficiently ameliorated mitochondrial dysfunction followed by neuronal death caused by glutamate-induced oxidative stress in cultured neurons. Consistent with this effect, MK-X significantly decreased caspase-3 cleavage and nuclear translocation of apoptosis-inducing factor induced by glutamate. MK-X completely mimicked the effect of EPO on multiple activation of JAK2 and its downstream PI3K/AKT and ERK1/2 signaling pathways, and this signaling process was involved in the neuroprotective effect of MK-X. Furthermore, MK-X and EPO induced similar changes in the gene expression patterns under glutamate-induced excitotoxicity. Interestingly, the most significant difference between MK-X and EPO was that MK-X better penetrated into the brain across the brain–blood barrier than did EPO. In conclusion, we suggest that MK-X might be used as a novel drug for protection from brain injury caused by ischemic stroke, which penetrates into the brain faster in comparison with EPO, even though MK-X and EPO have similar protective effects against excitotoxicity.

Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer’s disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ oligomers level between patient groups with mild or moderate cognitive decline (n = 39) and an age-matched normal control group (n = 21) by immunoblot analysis and comparing the levels of Aβ by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of Aβ oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer Aβ*56 and 15-mer AβO, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge Aβ*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric Aβ proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.

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. [BMB Reports 2021; 54(6): 295-304]