The L1 cell adhesion molecule affects protein kinase D1 activity in the cerebral cortex in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by deposition of β-amyloid protein (Aβ), neurofibrillary tangles and cognitive deficits resulting from neuronal cell death. In search for the molecular underpinnings of the disease, we were interested in the relationship between Aβ, L1 cell adhesion molecule and protein kinase D1 (PKD1), which are not only implicated in neural development and functional maintenance in the adult, but are also neuroprotective under pathological conditions. Based on our observations that L1 and phosphorylated, i.e. activated, protein kinase PKD1 (pPKD1) co-localize in cultured neurons, we investigated the functional relationship between L1 and pPKD1 in the frontal lobe of an AD human cortical tissue microarray, and found increased and positively correlating levels of both molecules when compared to a non-affected human brain. Also in the APP_SWE mouse model of AD, L1 and pPKD1 levels were increased in the frontal lobe. To investigate whether L1 influences PKD1-based functions in AD, cultured cortical neurons were stressed with either H₂O₂ or oligomeric Aβ₁₋₄₂, in the presence or absence of recombinant L1 extracellular domain, and PKD1 phosphorylation was measured. As indicated by the cell viability assay, L1 maintained neuronal survival under oxidative stress and under application of oligomeric Aβ₁₋₄₂, when PKD1 activity was inhibited, suggesting that L1 ameliorates some aspects of Aβ₁₋₄₂ pathology in parallel with reducing PKD1 function.