Effects of cell-type specific expression and aberrant processing of apolipoprotein E4 in the brain. Astrocyte-secreted apolipoprotein E (apoE) is internalized by neurons, but apoE4 expression in astrocytes has been associated with endoplasmic reticulum (ER) stress that may impair astrocyte function. Astrocyte-secreted apoE4 has also been associated with decreased blood–brain barrier (BBB) integrity via signaling in pericytes, decreased synapse development, and alterations in inflammatory response. A smaller proportion of brain apoE expression is attributed to neurons: apoE4 expressed in neurons (but not that internalized from astrocytes) is highly susceptible to cleavage by apoE cleaving enzyme (AECE) in the secretory pathway, becoming AECE-cleaved apoE4 missing C-terminus residues 272 to 299 (apoEΔ272–299). This cleavage product is capable of escaping the secretory pathway, self-aggregating in the cytosol, increasing tau fibrillization, interfering with mitochondrial function and motility, and impairing neurogenesis. In neurons, full-length apoE4 has been associated with decreased dendritic arborization and impairment of receptor trafficking. ETC, electron transport chain.