NGF AND BDNF DYSMETABOLISM IN A TRANSGENIC RAT MODEL OF ALZHEIMER’S DISEASE

The levels of NGF and BDNF neurotrophins are compromised in Alzheimer's disease; however, the causes and progressive evolution of these changes are not completely understood. We used the McGill-R-Thy1-APP rat model of Alzheimer's disease-like pathology, which progressively accumulate intraneuronal Aβ peptide, exhibit amyloid plaques and cognitive deficits to explore the evolution of NGF and BDNF deregulation and the impact on cholinergic synapses during the progression of Aβ pathology. Animals belonged to one of three groups: young, pre-plaque, transgenic rats (3–6 months), middle-aged (13–15 months) and old (18–21 months) post-plaque McGill-R-Thy1-APP rats. Age-matched wild type rats, used as controls, were non-transgenic littermates (hAPP negative). Neurochemical analyses revealed a differential dysregulation of the neurotrophins NGF and BDNF in the cortices of McGill-R-Thy1-APP transgenic rats. While BDNF mRNA levels were significantly reduced at very early stages of the amyloid pathology (3–6 months), before amyloid plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Surprisingly, the protein levels of the NGF precursor, proNGF, were increased despite the normal expression of NGF mRNA. Alterations in the NGF metabolic pathway affecting proNGF maturation, explain the upregulation of proNGF. The alterations in proNGF proteases and regulators were detected in middle-aged (13–15 months) and old (18–21 months) homozygous McGill APP transgenic rats, when extensive intracellular Aβ and extracellular amyloid plaques are present. In parallel, intraneuronal Aβ leads to significant reductions in BDNF mRNA expression, which further correlate with learning and memory deficits. The reduction in BDNF levels precedes the NGF dysmetabolism and the decline in VAChT-immunoreactive boutons, which occurs at the post-plaque stage. The reduction in BDNF mRNA occurs at very early stages of amyloid pathology, before plaques appeared and correlates with cognitive deficits, consistent with human studies (Peng et al., 2005b, Buchman et al., 2016). A marked dysregulation of the NGF metabolic pathway take place at advanced stages with extracellular amyloid plaques, similar to that previously found in the brains of Alzheimer's disease patients (Bruno et al, 2009a; Bruno et al, 2009b) and in Down syndrome individuals with dementia (Iulita et al, 2014c).