Apolipoprotein E (apoE) is found in amyloid plaques and neurofibrillary tangles 
(NFTs) in Alzheimer's disease (AD) brains, but its role in their pathogenesis is 
unclear. Previously, we found C-terminal-truncated fragments of apoE in AD 
brains and showed that such fragments can cause neurodegeneration and can induce 
NFT-like inclusions in cultured neuronal cells and in transgenic mice. Here, we 
analyzed apoE fragmentation in brain tissue homogenates from transgenic mice 
expressing apoE3 or apoE4 in neurons [neuron-specific enolase (NSE)-apoE] or 
astrocytes [glial fibrillary acidic protein (GFAP)-apoE] by Western blotting. 
The C-terminal-truncated fragments of apoE accumulated, in an age-dependent 
manner, in the brains of NSE-apoE4 and, to a significantly lesser extent, 
NSE-apoE3 mice; however, no fragments were detected in GFAP-apoE3 or GFAP-apoE4 
mice. In NSE-apoE mice, the pattern of apoE fragmentation resembled that seen in 
AD brains, and the fragmentation was specific for certain brain regions, 
occurring in the neocortex and hippocampus, which are vulnerable to AD-related 
neurodegeneration, but not in the less vulnerable cerebellum. Excitotoxic 
challenge with kainic acid significantly increased apoE fragmentation in 
NSE-apoE4 but not NSE-apoE3 mice. Phosphorylated tau (p-tau) also accumulated in 
an age-dependent manner in NSE-apoE4 mice and, to a much lesser extent, in 
NSE-apoE3 mice but not in GFAP-apoE3 or GFAP-apoE4 mice. Intraneuronal p-tau 
inclusions in the hippocampus were prominent in 21-month-old NSE-apoE4 mice but 
barely detectable in NSE-apoE3 mice. Thus, the accumulation of potentially 
pathogenic C-terminal-truncated fragments of apoE depends on both the isoform 
and the cellular source of apoE. Neuron-specific proteolytic cleavage of apoE4 
is associated with increased phosphorylation of tau and may play a key role in 
the development of AD-related neuronal deficits.