Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology Chunsheng Wang, a Wilkie A. Wilson, a,b Scott D. Moore, c,d Brian E. Mace, e,f Nobuyo Maeda, g Donald E. Schmechel, b,e,f and Patrick M. Sullivan e,f, * a Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA b Division of Neurology, Durham Veterans Affairs Medical Center, Durham, NC 27705, USA c Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA d Division of Psychiatry, Durham Veterans Affairs Medical Center, Durham, NC 27705, USA e Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC 27710, USA f Bryan Alzheimer’s Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA g Department of Pathology, University of North Carolina, Chapel Hill, NC 27599, USA Received 22 June 2004; revised 29 September 2004; accepted 21 October 2004 Available online 15 January 2005 The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer’s disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apolipoprotein (apo) E3 and apoE4 targeted replacement (TR) mice for changes in synaptic integrity. ApoE4 mice displayed significantly reduced excita- tory synaptic transmission and dendritic arborization. Despite these changes there were no signs of gliosis, amyloid deposition or neuro- fibrillary tangles in these mice. To our knowledge, this is the first study to suggest that cognitive deficits in APOE*4 carriers are due to inherent defects in synaptic function that appear prior to any age- dependent markers of neuropathology. D 2004 Elsevier Inc. All rights reserved. Keywords: Alzheimer; EPSP (excitatory postsynaptic); Cognitive; Transmission; Morphometry; Amygdala Many studies suggest that apoE maintains synaptic integrity in the central nervous system (CNS) (Masliah et al., 1996; Poirier, 1994; Raber et al., 2000) and that the apoE4 isoform is less efficient than apoE3 in this capacity. In the periphery, apoE maintains cholesterol and fat homeostasis; however, its function in the brain remains unclear. The human APOE gene encodes three common alleles, designated APOE*2 , E*3 and E*4 . The APOE*4 allele is associated with an increased risk of AD and a lower average age of onset (Poirier et al., 1993; Saunders et al., 1993) compared to the APOE*3 allele. Surprisingly, cognitive deficits are present in APOE*4 carriers decades before any diagnosis of dementia is made (Dik et al., 2001; Reiman et al., 2004; Snowdon et al., 1996). Hippocampal volumes are significantly smaller in APOE*4 middle-aged persons (asympto- matic for AD) (Plassman et al., 1997) and approximately 35% of early AD patients exhibit amygdala atrophy based on MRI morphometry (Cuenod et al., 1993). Although cholinergic deficits can be detected in nondemented carriers of an APOE*4 allele (Allen et al., 1997; Berr et al., 1996), apoE’s role in maintaining synaptic integrity in the limbic system remains to be determined. The entorhinal cortex, hippocampus, and amygdala are all critical limbic structures involved in memory formation that become damaged early in AD. The amygdala functions primarily to mediate emotional stimuli, in particular, fear conditioning. Hamann et al. (2002) found significant impair- ments in fear conditioning in AD patients compared to controls, providing evidence that the amygdala is vulnerable to neuro- degeneration. Recent studies have shown that the amygdala is required for learning, memory formation, and hippocampal plasticity (Akirav and Richter-Levin, 2002; Fried et al., 2001; Richter-Levin and Akirav, 2003). We are interested in determining what role apoE plays in maintaining amygdala– hippocampal synaptic integrity, prior to the onset of any defined neuropathology. In the early stages of AD, considerable loss of synapses occurs in the hippocampus followed by losses in the neocortex (Masliah et al., 1994; Sze et al., 1997). Although plaques and tangles have been implicated as causative factors in AD, the decline in synaptic function (loss of synapses) is the strongest correlate of cognitive decline in AD (Terry et al., 1991). In fact, animal studies (Buttini 0969-9961/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2004.10.013 * Corresponding author. Department of Medicine, Division of Neuro- logy, Duke University Medical Center, Box 2900, Durham, NC 27710, USA. Fax: +1 919 684 6514. E-mail address: p.sullivan@duke.edu (P.M. Sullivan). Available online on ScienceDirect (www.sciencedirect.com). www.elsevier.com/locate/ynbdi Neurobiology of Disease 18 (2005) 390 – 398