BACE1 SUBSTRATES IN PERIPHERAL SOMATOSENSORY FUNCTION

The β-site APP cleaving enzyme 1 (BACE1) plays a central role in the generation of amyloid-β peptides in Alzheimer’s disease. Beyond its involvement in Alzheimer’s pathology, increasing evidence suggests a role of BACE1 in peripheral sensory processing. BACE1 knockout mice show impaired formation of muscle spindles, reduced numbers of Pacinian corpuscles in the skin, and deficits in peripheral nerve myelination. To investigate the contribution of BACE1 to peripheral mechanosensors, structural and molecular alterations were analyzed in glabrous skin and dorsal root ganglia (DRGs) of BACE1-deficient mice. In hind paw skin, immunofluorescence-based quantification revealed a significant reduction in Merkel cell numbers in BACE1 knockout mice compared to wild-type littermates. To assess alterations at the level of sensory afferents, RNAscope-based analyses were performed in DRGs. While overall DRG neuron numbers remained unchanged, specific alterations were detected in TrkC- and Ptgfr-expressing neuronal subpopulations associated with Aβ-SAI neurons that innervate Merkel cells. As BACE1 processes multiple substrates implicated in peripheral sensory development, potential downstream mechanisms were addressed. Accordingly, candidate BACE1-dependent pathways were investigated. Combined RNAscope and immunofluorescence analyses in glabrous skin assessed the spatial expression of BACE1, Nrg1, SEZ6, and ErbB2/3/4 within and in the vicinity of the Merkel cell–neurite complex. In addition, Merkel cell distribution was analyzed in SEZ6-deficient mice using the same skin-based quantification approach.