Brain Cholinergic Markers and Tau Phosphorylation are Altered in Experimental Type 1 Diabetes: Normalization by Electroacupuncture

Abstract

Diabetes often correlates with tau phosphorylation and the development of Alzheimer's disease. Both are associated with brain cholinergic dysfunction that could benefit from nerve growth factor (NGF)-based therapies. Electroacupuncture (EA) improves brain NGF availability and action. Here we assessed the variations of NGF and tau phosphorylation in the cortex and hippocampus, as well as the expression of choline acetyltransferase in the basal forebrain following diabetes induction and EA in adult rats. We found that EA counteracts diabetes-associated tau hyperphosphorylation and decreases in NGF and choline acetyltransferase, suggesting a possible beneficial effect of EA on brain cholinergic system in diabetes.

The mature/pro nerve growth factor ratio is decreased in the brain of diabetic rats: Analysis by ELISA methods

“…Our data on experimental diabetes point to an early reduction in the mNGF/proNGF ratio in the hippocampus and cortex of diabetic rats, which is evident at 4 weeks and lasts until 8 weeks after diabetes induction. We previously demonstrated that 4 weeks after STZ treatment there was a significant reduction in neurons expressing cholinergic markers, such as the NGF receptor tyrosine kinase A (TrkA) and ChAT, in the medial septum (MS) (Rocco et al, 2013). In the present manuscript, we extended our observations to a later time-point (8 weeks), confirming the STZ-induced depletion of ChAT-expressing neurons and demonstrating a significant loss of p75 NTRexpressing cells in the MS.…”

“…It has previously been shown that proNGF acts as a proapoptotic inducer, by specifically challenging the p75 NTR , in BFCN (Volosin et al, 2006). Experimental DE in rats is characterized by impaired cholinergic NGF-related features, such as the loss of septal neurons expressing ChAT and TrkA (Rocco et al, 2013) or the increase in proNGF binding to the p75 NTR -sortilin receptor complex in the hippocampus (Soligo et al, unpublished observation). Interestingly, in the present paper we found a reduction in the number of p75 NTR -positive cells after DE induction, suggesting that in pathological conditions an altered mNGF/proNGF ratio is accompanied by altered receptor expression.…”

“…Direct cerebral effects of metabolic aberrations caused by DM result in a diabetes durationrelated cognitive decline, so-called primary DE, which has been reported to predispose patients to Alzheimer's disease (AD) (Sims-Robinson et al, 2010). Indeed, a key point emerging from clinical and basic research on DE is that it shares common pathological characteristics with AD (Kroner, 2009), including an early involvement of the brain cholinergic system (Rocco et al, 2013;Sherin et al, 2012;Sposato et al, 2007;Welsh and Wecker, 1991). Our data on experimental diabetes point to an early reduction in the mNGF/proNGF ratio in the hippocampus and cortex of diabetic rats, which is evident at 4 weeks and lasts until 8 weeks after diabetes induction.…”

“…Western blot densitometry data (n ¼4) were obtained by normalization of the single specific proNGF band with respective GAPDH band and expressed as percentage of control group. Korsching et al, 1985;Seiler and Schwab, 1984) and evidence that this neuronal system is affected early in AD patients (Cuello et al, 2010;Hefti and Weiner, 1986;Olson, 1993) -as well as in experimental models of DE (Rocco et al, 2013;Sposato et al, 2007) -led scientists and clinicians to hypothesize that NGF represents a feasible therapeutic target for diseases characterized by cholinergic neurodegeneration (recently reviewed in: Aloe et al, 2012;Manni et al, 2013). As it has been found that the precursor form of NGF (proNGF) acts as a distinct ligand by binding to a receptor complex consisting of the p75 NTR and sortilin to initiate cell death (Hempstead, 2014;Jansen et al, 2007;Nykjaer et al, 2004), it has been suggested that different neurodegenerative pathologies may be characterized by an abnormal mNGF/proNGF ratio.…”

“…We then selected appropriate antibodies, used them in ELISA and checked for their specificity. Finally, since several reports describe the presence of brain cholinergic dysfunctions in diabetic encephalopathy (DE) (Kamboj et al, 2008;Rocco et al, 2013;Sherin et al, 2012;Sima, 2004;Wahba and Soliman, 1988;Welsh and Wecker, 1991), which could be associated with deregulation in NGF maturation (Rocco et al, 2013;Sposato et al, 2007), we validated our newly-developed ELISA in a study of the dynamics of mNGF/proNGF contents in rat brain during the development and early progression of experimental diabetes.…”