Role of Prokineticin 2 in Metal Neurotoxicity - Abstract This administrative supplement proposal aims to uncover a novel compensatory neuroprotective mechanism of prokineticin 2 (PK2) signaling within the context of environmentally linked Alzheimer's disease-related dementia (ADRD). ADRD represents a significant subset of dementia conditions, primarily characterized by the presence of Alzheimer's disease (AD) pathology in the brain, including a range of cognitive impairments, memory deficits, and behavioral changes that affect daily life and functioning. AD, the most common form of dementia, is characterized by the accumulation of amyloid-beta (Aβ) plaques, abnormal tau protein tangles, chronic neuroinflammation, neuronal loss, and synaptic disruption. These pathological changes contribute to cognitive decline, memory loss, and behavioral symptoms in AD patients. The olfactory system is closely connected to brain regions involved in memory and cognition, and growing evidence indicates that olfactory dysfunction often occurs in the early stages of AD, frequently even preceding cognitive symptoms. Exposure to the environmental metal manganese (Mn) has also garnered attention in the context of AD/ADRD research. Chronic exposure to high levels of Mn, often associated with occupational settings, has been linked to olfactory dysfunction, cognitive impairment, and neurological symptoms reminiscent of AD. Despite the established link between olfactory dysfunction and memory-cognitive impairments, the exact molecular mechanisms responsible for the compromised olfaction and cognition in environmentally linked AD have not been fully elucidated. As outlined in our parent R01 proposal, we recently reported rapid upregulation of the neuropeptide prokineticin 2 (PK2) during early-stage Mn neurotoxicity, serving as a compensatory response to protect against neurodegeneration through pro-survival pathways. Additionally, our preliminary findings demonstrate that stimulating PK2 signaling led to a significant increase in glial-derived neurotrophic factor (GDNF) expression and release from astrocytes. Thus, we hypothesize that cognitive deficits, impaired OB function, and Aβ/tau pathology in AD may result from reduced PK2-GDNF-mediated compensatory signaling in the brain. Additionally, chronic Mn exposure may further deplete brain PK2-GDNF signaling, thereby intensifying ADRD-related pathology. To test this hypothesis, we will pursue the following specific aims: (i) Map the spatial and temporal expression of PK2-GDNF and their receptors across the cortex, hippocampus, OB, and basal ganglia regions, and establish functional correlations with region- specific neuronal susceptibility, the accumulation of Aβ/tau pathology, olfactory dysfunction, and cognitive deficits in the HTAP mouse model of AD; and (ii) Examine whether chronic exposure to Mn amplifies the depletion of hippocampal PK2-GDNF protective signaling, consequently exacerbating disease progression in HTAP mice. Overall, we predict that our proposed studies will provide novel mechanistic insights into metal- induced olfactory and cognitive dysfunction and its role in the pathogenesis of environmentally linked ADRD and will offer a novel therapeutic strategy.
