Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AßPP metabolites in the Tg2576 mouse model of Alzheimer's disease.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder which is the most common cause of dementia in the elderly today. One of the earliest symptoms of AD is olfactory dysfunction. The present study investigated the effects of amyloid ß precursor protein (AßPP) metabolites, including amyloid-ß (Aß) and AßPP C-terminal fragments (CTF), on olfactory processing in the lateral entorhinal cortex (LEC) using the Tg2576 mouse model of human AßPP over-expression. The entorhinal cortex is an early target of AD related neuropathology, and the LEC plays an important role in fine odor discrimination and memory. Cohorts of transgenic and age-matched wild-type (WT) mice at 3, 6, and 16months of age (MO) were anesthetized and acute, single-unit electrophysiology was performed in the LEC. Results showed that Tg2576 exhibited early LEC hyperactivity at 3 and 6MO compared to WT mice in both local field potential and single-unit spontaneous activity. However, LEC single-unit odor responses and odor receptive fields showed no detectable difference compared to WT at any age. Finally, the very early emergence of olfactory system hyper-excitability corresponded not to detectable Aß deposition in the olfactory system, but rather to high levels of intracellular AßPP-CTF and soluble Aß in the anterior piriform cortex (aPCX), a major afferent input to the LEC, by 3MO. The present results add to the growing evidence of AßPP-related hyper-excitability, and further implicate both soluble Aß and non-Aß AßPP metabolites in its early emergence.