Apolipoprotein E Role in Maintaining the Integrity of the Aging Central Nervous System

Apolipoprotein E (apoE) is involved in the development and regeneration of the central nervous system (CNS). Recent studies have shown that the expres sion of allele e4 of APOE is a major risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder associated with synaptic loss, amyloid deposition and disruption of the neuronal cytoskeleton. In order to better understand the mechanisms by which apoE is involved in AD, it is necessary to understand the physiological role of this molecule in the intact CNS. For this purpose, we studied the fate of synaptic and dendritic populations during aging and after injury to the CNS in apoE-deficient (knockout) mice. In apoE deficient homozygous mice, there was an age-dependent 15%–40% loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus, when compared to controls. Dendritic alterations were observed as early as 4 months of age. Ultrastructural analysis revealed extensive dendritic vacuolization and disruption of the endomembrane system and cytoskeleton in apoE-deficient homozygous mice. The dendritic damage was accompanied by a decreased immunoreactivity for cytoskeletal markers α and β tubulin (but not kinesin) in the cell bodies and processes of neurons of apoE-deficient mice. In addition, apoE-deficient homozygous mice showed a delay in the patterns of reinnervation of the outer molecular layer of the hippocampal dentate gyrus after perforant pathway transection, and in the neocortex after intraperitoneal kainic acid injection. These results support the contention that apoE might play an important role in maintaining the stability of the synapto-dendritic apparatus, and that altered or deficient functioning of this molecule could underlie the synaptic and cytoskeletal alterations observed in AD.