Thursday, April 18, 2024
4/18/2024
PROJECT SUMMARY: Understanding the causality between risk factors and early symptoms is crucial to early and differential diagnosis of Alzheimer’s disease (AD). Expression of the ¿-4 allele of human apolipoprotein E (APOE4) 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 APOE4 gene evince OD symptoms before AD pathogenesis, indicating a role of APOE4 in functional disorders of the olfactory system. However, the pathophysiological mechanisms underlying the APOE-4 actions on olfaction remain unclear. We hypothesize that APOE4 disrupts astrocyte-neuron interaction leading to excitation-inhibition imbalance and synaptic dysfunction in the olfactory bulb (OB) to cause OD at the early stage of AD based on the following evidence. First, network dysfunction has been observed in the OB of APOE4 mice as young as 6-month-old. Consistently, our preliminary data show reduced odor sensitivity in APOE4 mice at this age. Second, APOE is predominantly expressed by astrocytes surrounding each OB glomerulus. Our pilot studies reveal morphological and physiological deficits in the glomerular astrocytes in APOE4 mice. Third, as a key element of the partite synapses, astrocytes play pivotal roles in uptake of neurotransmitters from the synaptic clefts. Our preliminary evidence demonstrates upregulation of both excitatory and inhibitory synaptic responses in the principal OB output neurons of APOE4 mice, congruent with dysfunction of glomerular astrocytes. Finally, our observed neuronal hyperactivities in the mitral cell layer of awake APOE4 mice, supporting excitation-inhibition imbalance in the OB leading to OD. Three specific aims are proposed to test our central hypothesis. Aim 1: Determine effects of APOE4 or modulating astrocytic functions on odor detection/sensitivity. Aim 2: Characterize astrocytic modulation of OB neuronal activities and APOE4 effects. Aim 3: Investigate astrocytic modulation of synaptic transmission and APOE4 effects in the OB. The proposed work at the cellular, circuit, and behavioral levels is designed to fill gaps in our knowledge on astrocytic modulation of synaptic processing of olfactory signals in the OB and its roles in the APOE4-associated OD. Our findings will potentially shed light on development of effective strategies for early and accurate diagnosis of AD in the APOE4-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.
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