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Abstract Details

Identifying The Normal Function of Amyloid-Beta and Its Role in Alzheimer's Disease
Aging, Dementia, Cognitive, and Behavioral Neurology
P5 - Poster Session 5 (11:45 AM-12:45 PM)
7-009
We previously found that the hippocampal heme content was more than double in brain autopsy from AD patients compared to the age-matched controls, suggesting abnormal heme and iron homeostasis. We also found that abnormal heme metabolism compromises mitochondrial function. More direct evidence for the role of abnormal heme metabolism in AD came from our findings that Ab binds with Regulatory Heme (RH) and induces heme synthesis by the mitochondria and increases iron uptake. These observations are consistent with Ab binding with RH in situ and demonstrate that Ab binding with RH has functional implications that can alter cellular activity. RH regulates pathways other than heme synthesis, which, if compromised, could contribute to Ab’s neurotoxicity: 1) cellular response to oxidative and chemical stresses through Bach1/Nrf2/Keep1; 2) cytoprotection and energy metabolism through GAPDH; 3) microRNA processing and gene regulation through DGCR8.
Amyloid-b (Ab40 and Ab42) peptides are implicated in neurotoxicity and dementia of Alzheimer’s disease (AD). They are naturally produced in the healthy brain; however, their normal function is unknown. This gap of knowledge complicates our understanding of the insidious neurotoxic mechanism of Ab.
Human SHSY5Y cells were differentiated to cholinergic neurons and used for experiments and data collection. 
Our preliminary data show that Ab40 and Ab42 affect the intracellular levels of RH. While Ab40 lowers intraneuronal RH by 50 % (P<0.03), Ab42 increases RH by »400% (P<0.02) compared to the controls. This difference between both peptides was eliminated by inhibiting HO. 
We propose that Ab controls RH homeostasis by enhancing RH degradation (Ab40) and/or sequestering RH (Ab42), causing RH deficiency. RH deficiency compromises neuronal energy metabolism, response to stress, and leads to iron overload by neurons. These findings are expected to enhance our understanding for the insidious mechanism of Ab neurotoxicity.
Authors/Disclosures
Rachel Hunsucker
PRESENTER
Ms. Hunsucker has nothing to disclose.
Hani Atamna, PhD (California University of Science and Medicine (CUSM)) Dr. Atamna has nothing to disclose.
Triet Vo, Other Mr. Vo has nothing to disclose.