Cellular and circuit mechanisms underlying APOE-4 effects on olfaction.

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PROJECT SUMMARY: Understanding the relationship between risk factors and early symptoms is crucial to early and differential diagnosis of Alzheimer’s disease (AD). Expression of the ϵ-4 allele of human apolipoprotein E (APOE-4) gene, the strongest genetic risk factor for development of the episodic late-onset AD, associates tightly with the earliest AD symptom - olfactory deficit (OD) in humans. Animals expressing the human APOE-4 gene evince OD symptoms before AD pathogenesis, indicating a role of APOE-4 in functional disorders of the olfactory system. However, the pathophysiological mechanisms underlying the APOE-4 effects on olfaction remain unclear. We hypothesize that APOE-4 dysregulates neural circuits leading to excitation-inhibition imbalance and neural hyperactivity in the anterior olfactory nucleus (AON) to cause OD at the early stage of AD based on the following evidence. First, the hallmark AD pathologies appear in the AON in the Braak stages 0 and I of the disease and increase with AD severity. APOE-4 elevates AD pathogenesis. Second, the severity of AD pathology (especially tau hyperphosphorylation) in the AON correlates linearly with the copies of APOE-4 allele. Third, AON has direct interconnections with the olfactory bulb, piriform cortex, hippocampus, amygdala, and lateral entorhinal cortex. All these olfactory centers exhibit vulnerability to AD pathogenesis at early stages in humans and neuronal hyperexcitability in transgenic animals with humanized APOE-4 genotype. Based on our preliminary data and the massive interconnections of AON with all other olfactory brain centers via glutamatergic transmission that is particularly susceptible to detrimental effects of APOE-4, we hypothesize that APOE-4 causes excitation-inhibition imbalance in the AON and dysfunction of related neural circuits leading to OD. Three specific aims are proposed to test our central hypothesis. Aim 1: Determine APOE-4 impact on olfaction-dependent behaviors. Aim 2: Investigate APOE-4 effects on AON neuronal excitability. Aim 3: Characterize APOE-4 influence on synaptic processing in the AON. The proposed work is designed to fill gaps in our knowledge on the mechanistic relationship between APOE-4, a well-established genetic risk factor of LOAD, and OD at the cellular, circuit, and behavioral levels. Our findings will potentially shed light on development of effective strategies for early and accurate diagnosis of AD in the APOE-4- carrying or even broader populations. Since AD progressively impairs patient’s cognitive and other mental abilities for years to decades thus significantly compromises the quality of life in the senior populations in the US and worldwide, early and accurate diagnosis of this neurodegeneration will significantly benefit the affected populations and their societies at the medical, economical, emotional, and social levels.