FOLATE PREVENTS THE DETRIMENTAL EFFECTS OF OLIGOMERIC Aβ ON INSULIN RECEPTOR LOCALIZATION AND FUNCTION AND LONG-TERM POTENTIATION

Abstract

Oligomeric Aβ peptide toxicity may contribute to neuronal dysfunction and neurodegeneration in Alzheimer's disease (AD). For example, we showed that Aβ toxicity may underlie AD-associated “Type 3 Diabetes” by inhibiting Kinesin-5, thereby preventing the normal localization and function of the insulin receptor and the glucose transporter (AAIC, 2016). Aβ treatment acutely inhibits long-term potentiation (LTP) and results in synaptic loss, which is mediated in part by Aβ-mediated inhibition of Kinesin-5, likely via mis-localization of key neurotransmitter receptors. In view of evidence that folic acid/folate supplementation may delay/reduce the incidence of AD, we sought to determine whether folate can prevent the toxic effects of Aβ on insulin receptor localization and function and on LTP. N2A cells in culture were co-treated with folate (2 μM) and Aβ42 peptide (2 μM), and insulin receptor localization, function, and phosphorylation were assessed by immunocytochemistry following insulin challenge. LTP in the stratum radiatum was also assessed in mouse brain slices by response to high frequency (2 x 100 Hz) stimulation (HFS) of the Schaffer collateral axons. LTP was strongly inhibited by 100 nM oligomeric Aβ peptide. In the presence of Aβ peptide, folate (2 μM) was added either for 40 min before the HFS (short) or for at least 60 min prior to the HFS and for the remaining 60 min of the recording period (long). N2A cells treated with oligomeric Aβ (48 h) alone exhibited decreased insulin receptor activation (phosphorylation), and the majority of the insulin receptor localized to small aggregates associated with the cis-Golgi, rather to the cell surface. N2A cells co-treated with folate and Aβ maintained normal cell surface localization and function/phosphorylation of the insulin receptor in response to insulin stimulation. ‘Long’ treatment of the mouse brain slices, but not ‘short’ treatment, with folate restored LTP in the presence of oligomeric Aβ. Folate pre-treatment blocks oligomeric Aβ-mediated inhibition of neuronal metabolism and memory function. These results provide a mechanism by which folate can prevent the Aβ toxicity and reinforce the concept that folate supplementation may slow the development of AD.