SENSORY FUNCTIONS OF THE Β-SECRETASE BACE1 IN KNOCKOUT MICE

The β-site APP cleaving enzyme 1 (BACE1) accounts for the rate-limiting step in the production of toxic β-amyloid (Aβ) in Alzheimer’s disease (AD). Pharmacological intervention targeting BACE1 did not improve cognition in AD patients. Therefore, unraveling the physiological functions of the β-secretase is of particular importance. Increasing evidence suggests an involvement of BACE1 in peripheral sensory processing, including proprioception, pain and thermosensation. BACE1^-/- mice have been reported to exhibit altered thermal thresholds (heat), a decreased number and impaired formation of muscle spindles, reduced number of Pacinian corpuscles in the skin, as well as deficits in myelination of peripheral nerves. Further investigating BACE1’s role in mechanosensation, we found significantly reduced numbers of Merkel cells in the walking pads of glabrous skin in BACE1^-/- mice. Using a comprehensive battery of sensory tests (Hot Plate, Cold Plate, Hargreaves, Tail Flick and von Frey), we found that BACE1^-/- mice exhibited reduced sensitivity to heat, while their responses to noxious cold (0 °C cold plate) and mechanical stimulation (von Frey test) appeared unaffected. We hypothesized that von Frey-evoked withdrawal thresholds, which reflect nociceptive mechanical sensitivity, may be unaffected by a reduced number of Merkel cells. To assess BACE1-dependent sensory processing beyond nociception, we employed two preference-based behavioral paradigms. Thermal preference was examined using a thermal gradient ring and tactile preference was assessed using a newly established texture gradient ring paradigm.