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Volume 08
Journal of Alzheimers Disease & Parkinsonism
Alzheimer's Congress 2018
May 30-31, 2018
May 30-31, 2018 Osaka, Japan
10
th
World Congress on
Alzheimer's Disease & Dementia
Neuronal excitability changes produced by alzheimer’s related pathology and by its risk factors
Herman Moreno, Luna Buitrago and Sergio Angulo
SUNY Downstate Medical Center, USA
A
lzheimer’sDisease (AD) is characterized by synaptic dysfunction early in the progression of the disease. It remains unknown
the specific neuronal abnormalities produced by AD related pathology (Amyloid and Tau) to the Entorhinal Cortex (EC)-
hippocampus circuit, the region targeted earliest by AD. Here, we address this issue by studying mice that express mutated
human Amyloid Precursor Protein (hAPP) or mutated human Tau protein (hTau) or both in the EC. This approach allowed us
to investigate the two pathologies separately and together additionally we also studied mice expressing the main genetic risk
factor for AD (APOE4). Mice (APOE4) were compared to those expressing APOE3. The experiments showed that expression
of mutant hAPP in EC (EC-hAPP) produced a significant increase in the duration of spontaneous extracellular field potentials
in the superficial layers of both Medial EC and Lateral EC. We also observed that in EC-hAPP mice, pyramidal neurons of the
subiculum, which are monosynaptically excited by EC layer III/II neurons, showed miniature excitatory postsynaptic currents
having reduced amplitude, suggesting that the increased excitation observed in EC induced a compensatory negative feedback
in subicular projection neurons, a process known as synaptic homeostasis. Modeling of the EC-hippocampus microcircuits
indicates that EC hyperexcitability and subicular synaptic downscaling of mice expressing hAPP could be explained by EC
interneuron pruning. The functional changes produced in EC by the expression of mutant τ protein (P301L) manifested as
resistance to GABAA antagonist-induced hypersynchrony, but it did not, by itself, produce significant spontaneous activity
changes in EC-hippocampus circuits. Mice displaying both pathologies as early as 2.5 months of age had an intermediate and
subtler phenotype, predominantly driven by τ-pathology. An intriguing finding was the fact that mice expressing APOE4 had
a relatively similar phenotype that mice expressing hAPP. This is increased synchronous activity in LEC, but the mechanism
of such hypersynchrony is mediated by changes in GABAA receptors abnormalities in the pyramidal cell, and this is observed
late in the disease. Our findings demonstrate the significant role of the lateral and medial entorhinal cortices in the early stages
of AD where contrasting and complex interactions of APP, τ and APOE are observed.
Biography
Herman Moreno is an Associate Professor of Neurology and Pharmacology/Physiology at SUNY Downstate Medical Center, New York, USA.
herman.moreno@downstate.eduHerman Moreno
et.al., J Alzheimers Dis Parkinsonism 2018, Volume 8
DOI: 10.4172/2161-0460-C4-045