Memory and Neurochemical Changes Associated with Aging, Neurogenesis, and Neurodegeneration: Potential Targets for Modulation

• Grant number: 24/20438-5
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2025
• End date: August 31, 2028
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Suzete Maria Cerutti
• Grantee: Suzete Maria Cerutti
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: Diogo de Oliveira Silva ; Janete Maria Cerutti

Abstract

Neural circuits in the hippocampal formation (HF) and prefrontal cortex (PFC) are particularly vulnerable to aging, the main risk factor for late-onset Alzheimer's disease (LOAD). Episodic-like memories (ELM) are also affected in both cases, making it crucial to characterize the neurochemical changes associated with the consolidation and persistence of EM, as well as the aging- and LOAD-related changes in these circuits. Factors such as cholinergic hypofunction and brain insulin resistance (IR) are also involved in aging and LOAD. In this context, this project aims to investigate: Experiment I - Assessment of changes associated with the formation and persistence of ELM in Wistar rats and C57BL/6 mice, young males (3 months), using a training protocol to integrate information about the event-context-time association (WWWhen). After protocol standardization, the effect of aging will be evaluated in middle-aged (12 months) and aged (24 months) animals (n=8-10/group/species). Samples of total brain, HF, and PFC will be collected at the end of training/tests and stored at -80°C. Immediate-early genes (arc and homer 1a) will be evaluated by in situ hybridization and qPCR, as well as proteins related to neuroprotection, memory persistence, oxidative stress, calcium signaling, and autophagy by immunoblotting and immunohistochemistry. The co-localization of cells (synaptic tagging) in the mentioned areas will also be analyzed. The data will guide subsequent analyses, including the inactivation of areas identified as fundamental for the process to confirm previous data. The effect of associating a new context (novelty) with the training (behavioral tagging) and the treatment with EGb will also be investigated in groups with deficits in ELM formation. Experiment II - The effect of aging and LOAD on the HF and PFC of young and old animals, controls and treated with EGb, from a previous study (FAPESP 2019-24614-4), which used two models: i) rats with induced brain insulin resistance (IR) by intracerebroventricular injection of streptozotocin (STZ icv), and ii) cholinergic-deficient mice with a reduction of 45% or 65% of VAChT expression (VAChT KDHET or KDHOM). Samples of HF and PFC will be analyzed by untargeted metabolomics (LC-MS) (n=4) and by the expression of proteins related to inflammation, neuroprotection, memory, Alzheimer's disease (AD), neurogenesis, apoptosis, autophagy, and insulin function by immunohistochemistry /immunofluorescence (n=4-6). Metabolomic results will be validated by immunoblotting and/or immunohistochemistry to identify potential therapeutic targets. (AU)