Correlation between cognitive deficits and A deposits in transgenic APP+PS1 mice Marcia N. Gordon a , David L. King b , David M. Diamond a,c , Paul T. Jantzen a , Kristal V. Boyett a , Caroline E. Hope b , Jaime M. Hatcher b , Giovanni DiCarlo a , W. Paul E. Gottschall a , Dave Morgan a, *, Gary W. Arendash b a Alzheimer’s Research Laboratory, Department of Pharmacology, University of South Florida, Tampa, FL 33612, USA b Alzheimer’s Research Laboratory, Department of Biology, University of South Florida, Tampa, FL 33612, USA c Stress and Memory Research Laboratory, Department of Psychology & VA Medical Center, University of South Florida, Tampa, FL 33612, USA Received 24 April 2000; received in revised form 25 October 2000; accepted 2 November 2000 Abstract Doubly transgenic mAPP+mPS1 mice (15–16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of A deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as A deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce A load. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Alzheimer’s disease; Transgenic mice; Learning and memory; Radial arm water maze; Amyloid load; A deposition 1. Introduction Alzheimer’s disease (AD) is characterized by progres- sive, severe cognitive deficits which include impaired mem- ory for recent events at an early stage of the disease process. Two pathologic characteristics of the disease are A peptide containing, congophilic amyloid plaques and neurofibrillary tangles [49]. Although the extent to which either of these features causes the dementia of Alzheimer’s disease re- mains unresolved, both have been correlated with the degree of cognitive decline in dementia [11,14,15,18,28,38,46]. One of the first to demonstrate a relationship between amy- loid and cognitive function was Blessed et al. [3]. However, this was disputed as primarily arising from an overall group difference between control and demented patients; the cor- relation disappeared when control cases were excluded [50]. In this study, synapse loss was argued to be the best corre- late of cognitive decline in dements. Roses [47] has men- tioned that because the presence of amyloid is required to diagnose AD, and its absence required for “control” cases, it would be impossible for amyloid not to correlate with dementia rating when control cases are included. One of the most careful studies found that both A deposits and neu- rofibrillary tangles in entorhinal cortex correlate with de- mentia rating, even when the control cases were excluded [11]. A very recent study [46] found that elevated A content in frontal cortex was predictive of declining cogni- tive function in a large panel of carefully collected elderly cases. The A elevations preceded neuritic pathology in this patient set. However, even this study did not report corre- lations between A measurements and dementia rating that excluded nondemented cases. Therefore, the relationship between A pathology and cognitive function in Alzhei- mer’s disease remains a point of contention (see commen- taries following [11]). A small fraction of Alzheimer’s cases results from in- heritance of an autosomal dominant mutation. Mutations in at least three genes can account for the disorder in inherited * Corresponding author. Tel.: +1-813-974-3949; fax: +1-813-974- 2565. E-mail address: dmorgan@hsc.usf.edu (D. Morgan). www.elsevier.com/locate/neuaging Neurobiology of Aging 22 (2001) 377–386 0197-4580/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0197-4580(00)00249-9