Human neurons can survive for over a century, but pathogenic mechanisms associated with aging lead to their premature loss. The initiating events of age-associated neuronal loss and the mechanisms of the transition from a stochastic loss of neurons into an organized, progressive loss of neurons that leads to neural system failure and clinical neurodegenerative disease remain to be defined. Recent evidence implicates increased burden of genomic lesions and the induction of innate immune signaling as two possible components underlying many neurodegenerative diseases. To elucidate fundamental mechanisms of neurodegeneration, we developed mouse lines that conditionally overexpress pathogenic and non-pathogenic isoforms of the human amyloid precursor protein (hAPP), exclusively in olfactory sensory neurons (OSNs) in the nose. We chose to model neurodegeneration in olfactory neurons because of the availability of powerful genetic tools to manipulate or interrogate these neurons in vivo in a cell type specific manner and their documented vulnerability to neurodegenerative disease. We found that half of the lines overexpressing each hAPP isoform exhibited marked neurodegeneration, which was rescued with suppression of transgene expression. Although the two neurodegenerative (Nd1 and Nd2) lines expressed hAPP isoforms exclusively in <1% of OSNs, we observed marked degeneration of OSNs (40% loss) and connected second order olfactory neurons (15% loss) not expressing the transgene, indicating propagation of degeneration in a non-cell autonomous manner. The other half of the mouse lines did not demonstrate neurodegeneration, in spite of expressing the same level of pathogenic or non-pathogenic hAPP mRNA and protein in each OSN. Next generation sequencing of sorted OSNs from the Nd1 line revealed a profound induction of innate immune signaling pathways in all OSNs that was not found in the non-neurodegenerative lines. Since innate immune signaling pathways can be evoked by double stranded RNA (dsRNA), we found evidence for complex chromosomal lesions, including inversions (which we demonstrated give rise to dsRNA), in the Nd1 and Nd2 lines, but not in the non-neurodegenerative lines. Moreover, we developed a a model of degeneration of OSNs evoked by expression of dsRNA encoding the non-pathogenic protein GFP to demonstrate sufficiency of dsRNA to evoke neurodegeneration. We have found increased expression of the dsRNA binding innate immune pattern recognition receptors (PRRs) MDA5 and PKR in human brains with Alzheimer's disease and ALS. Here, we propose to establish whether MDA5 and PKR are necessary to mediate propagated neurodegeneration in the Nd1 and Nd2 mouse lines, and in a model of degeneration of OSNs evoked by expression of dsRNA encoding the non-pathogenic protein GFP. These studies have potential to validate a novel mechanism of neurodegeneration based on the intrinsic activation of PRRs within neurons, and establish a molecular link between genomic lesions, the activation of innate immune signaling pathways, and progressive neurodegeneration.

Public Health Relevance

The staggering economic and emotional impact of neurodegenerative disease is projected to double in the next two decades, and no treatments are available. We have generated novel mouse lines with robust degeneration of a specific class of neurons, with subsequent propagation of degeneration to neurons connected in the same network in the setting of a profound induction of genes encoding an innate immune signaling pathway. We propose to determine whether two innate immune pattern recognition receptors are required to propagate neurodegeneration within a circuit in these mouse lines in order to validate these proteins as drug targets deserving further evaluation for therapeutic development of adult-onset neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS094861-01
Application #
9015860
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Corriveau, Roderick A
Project Start
2015-09-15
Project End
2017-08-31
Budget Start
2015-09-15
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$248,508
Indirect Cost
$98,508
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Dhilla Albers, Alefiya; Asafu-Adjei, Josephine; Delaney, Mary K et al. (2016) Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly. Ann Neurol 80:846-857