Differential spatial expression of peripheral olfactory neuron-derived BACE1 induces olfactory impairment by region-specific accumulation of beta-amyloid oligomer

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, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)-the initiating enzyme in A beta genesis-and beta-amyloid peptide (A beta), hallmarks of AD were analyzed. We found that an increase in BACE1 expression coincided with an elevation of amyloid-beta (A beta) 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 A beta 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 A beta 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.1

Distinct amyloid precursor protein processing machineries of the olfactory system

Processing of amyloid precursor protein (APP) occurs through sequential cleavages first by β-secretase and then by the γ-secretase complex. However, abnormal processing of APP leads to excessive production of β-amyloid (Aβ) in the central nervous system (CNS), an event which is regarded as a primary cause of Alzheimer's disease (AD). In particular, gene mutations of the γ-secretase complex—which contains presenilin 1 or 2 as the catalytic core—could trigger marked Aβ accumulation. Olfactory dysfunction usually occurs before the onset of typical AD-related symptoms (eg, memory loss or muscle retardation), suggesting that the olfactory system may be one of the most vulnerable regions to AD. To date however, little is known about why the olfactory system is affected so early by AD prior to other regions. Thus, we examined the distribution of secretases and levels of APP processing in the olfactory system under either healthy or pathological conditions. Here, we show that the olfactory system has distinct APP processing machineries. In particular, we identified higher expressions levels and activity of γ-secretase in the olfactory epithelium (OE) than other regions of the brain. Moreover, APP c-terminal fragments (CTF) are markedly detected. During AD progression, we note increased expression of presenilin2 of γ-secretases in the OE, not in the OB, and show that neurotoxic Aβ*56 accumulates more quickly in the OE. Taken together, these results suggest that the olfactory system has distinct APP processing machineries under healthy and pathological conditions. This finding may provide a crucial understanding of the unique APP-processing mechanisms in the olfactory system, and further highlights the correlation between olfactory deficits and AD symptoms. © 2017 Elsevier Inc.1

Effects of the Interparental Relationship on Adolescents’ Emotional Security and Adjustment: The Important Role of Fathers

We examined the mediational roles of multiple types of adolescents' emotional security in relations between multiple aspects of the interparental relationship and adolescents' mental health from ages 13 to 16 (N = 392). General marital quality, nonviolent parent conflict, and physical intimate partner violence independently predicted mental health. Security in the father-adolescent relationship, over and above security with the mother and security in regard to parent conflict, mediated the link from general marital quality to adolescents' mental health. With 2 exceptions, paths were stable for boys and girls, biological- and stepfathers, and Anglo- and Mexican Americans. The findings reveal the need to expand the traditional foci on parent conflict and relationships with mothers to include general marital quality and relationships with fathers. (PsycINFO Database Recor

Effects of the interparental relationship on adolescents’ emotional security and adjustment: The important role of fathers.

We examined the mediational roles of multiple types of adolescents’ emotional security in relations between multiple aspects of the inter-parental relationship and adolescents’ mental health from ages 13 to 16 (N = 392). General marital quality, non-violent parent conflict, and physical intimate partner violence independently predicted mental health. Security in the father-adolescent relationship, over and above security with the mother and security in regard to parent conflict, mediated the link from general marital quality to adolescents’ mental health. With two exceptions, paths were stable for boys and girls, biological- and step-fathers, and Anglo- and Mexican-Americans. The findings reveal the need to expand the traditional foci on parent conflict and relationships with mothers to include general marital quality and relationships with fathers