The amyloid precursor protein (APP) and APP‐like (APLP) material, as visualized with the Mab22C11 antibody, have previously been shown to be associated with radial glia in hypothalamus, which are known to promote neurite outgrowth. By Northern blot analysis, APP 695 mRNA levels increased steadily over hypothalamic development, APP 770 mRNA was transiently expressed at 12 days postnatally, and APLP mRNA was only weakly expressed in the hypothalamus. The developmental pattern of APP moeities in mouse hypothalamus and in fetal hypothalamic neurons in culture was compared with a presenilin 2 (PS2) related protein using an antibody developed against the N‐terminal part of PS2. By Western blot analysis, APP and PS2‐like immunoreactivity were visualized as a 100–130 and 52 kDa bands, respectively. An APP biphasic increase was observed during hypothalamic development in vivo. APP immunoreactivity was equally detected in neuronal and glial cultures, while PS2‐like material was more concentrated in neurons. A correlation between APP/APP‐like and PS2‐like levels was observed during development in vivo. While APP was mostly associated with membrane fractions, a significant portion of PS2‐like material was also recovered from cytosolic fractions in vitro. In contrast to native PS2 in COS‐transfected cells, the PS2‐like material did not aggregate after heating for 90 s at 90 °C. These results indicate a close association between APP and PS2‐like material during hypothalamic development in vivo, and suggest that neuronal and glial cultures may provide appropriate models to test their interactions.