The Reversal of Memory Deficits in an Alzheimer's Disease Model Using Physical and Cognitive Exercise

Abstract

Alzheimer's disease (AD) is the leading cause of dementia in the world, accounting for 50-75% of cases. Currently, there is limited treatment for AD. The current pharmacological therapy minimizes symptom progression but does not reverse brain damage. Studies focused on nonpharmacological treatment for AD have been developed to act on brain plasticity and minimize the neurotoxicity caused by the amyloid-beta (Aβ) peptide. Using a neurotoxicity model induced by Aβ in rats, the present study shows that physical (PE) and cognitive exercise (CE) reverse recognition memory deficits (with a prominent effect of long-term object recognition memory), decrease hippocampal lipid peroxidation, restore the acetylcholinesterase activity altered by Aβ neurotoxicity, and seems to reverse, at least partially, hippocampal tissue disorganization.

Keywords: Alzheimer’s disease; Aβ neurotoxicity; cognitive exercise; oxidative damage; physical exercise.

Figure 1

Experimental design. Rats were submitted to a stereotaxic surgery with the injection of Aβ or saline solution (sham surgery) in the hippocampus. Ten days after surgery, the time required for surgery recovery and Aβ aggregation, the training period started, being: physical exercise (PE), cognitive exercise (CE), or none (no intervention), during 4 weeks. Afterward, behavioral tests were performed to evaluate the object and social recognition memory and to monitor the general behavioral; after, the euthanasia was performed to brain tissue collection for histological and biochemical analyses. OR, object recognition memory test; SR, social recognition memory test; OF, open field; PM, plus maze.

Figure 2

The hippocampal Aβ infusion promotes Object Recognition (OR) memory deficit. PEs and CEs can revert the OR memory deficit caused by hippocampal Aβ infusion. (A) OR short-term memory (STM). (B) OR long-term memory (LTM). *P < 0.05; one-sample Student’s t-test (theoretical mean 50%). Data are presented as mean ± SD (n = 11–12/group). Tr, training.

Figure 3

The PE and CE interventions overcome OR LTM, but not STM, memory discrimination index (DI) deficit induced by Aβ protein. *P < 0.05, Kruskal–Wallis followed by Mann–Whitney test. (A) STM DI. (B) LTM DI. Data are presented as mean ± SD (n = 11–12/group).

Figure 4

Effects of hippocampal Aβ infusion, physical and CEs on social recognition (SR) memory. (A) The hippocampal Aβ infusion promotes SR memory deficit. PE and CE can promote SR memory consolidation in rats that received intrahippocampal Aβ infusion. (B) There are no differences on SR DI between the groups. *P < 0.05; one-sample Student’s t-test (theoretical mean 50%). Data are presented as mean ± SD (n = 11–12/group).

Figure 5

Aβ hippocampal infusion promotes reactive oxygen species (ROS; DCFH, A) and lipid peroxidation increase (TBARS, B); and promotes total antioxidant capacity (C) and acetylcholinesterase activity decrease (D). The PE and the CE performed during 4 weeks reverted the lipid peroxidation (B), and AchE activity (D) alterations. Data from ROS (DCFH, A) and TBARS (B) are presented as mean ± SD and were analyzed by ANOVA followed by Tukey’s test. Data from FRAP (C) and Acetylcholinesterase (AChE; D) are presented as median ± interquartile range and were analyzed by Kruskal–Wallis test followed by Dunn’s test. *P < 0.05, compared to control. ^#P < 0.05, compared to Aβ.

Figure 6

Control (A), PE (C) and CE (E) groups presented standard hippocampal morphology with tissue organization. Infusion of Aβ promotes hippocampal disorganization, vacuoles formation, and neuronal tissue loss (B). PE (D) and CE (F) improved hippocampal tissue morphology. Brain stained by hematoxylin-eosin (HE; magnification 10×). The arrows indicated vacuoles; the stars indicated tissue with normal organization, with cells in a parallel and layered position; and, the triangle indicated atrophy and tissue disorganization (A): Control group; (B): Aβ group; (C): PE group; (D): Aβ + PE group; (E): CE group; (F): Aβ + CE group.