Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized by amyloid (Aβ) aggregation, hyperphosphorylated tau, neuroinflammation, and severe memory deficits. Reports that certain boronic compounds can reduce amyloid accumulation and neuroinflammation prompted us to compare trans-2-phenyl-vinyl-boronic-acid-MIDA-ester (TPVA) and trans-beta-styryl-boronic-acid (TBSA) as treatments of deficits in in vitro and in vivo models of AD. We hypothesized that these compounds would reduce neuropathological deficits in cell-culture and animal models of AD. Using a dot-blot assay and cultured N2a cells, we observed that TBSA inhibited Aβ42 aggregation and increased cell survival more effectively than did TPVA. These TBSA-induced benefits were extended to C. elegans expressing Aβ42 and to the 5xFAD mouse model of AD. Oral administration of 0.5 mg/kg dose of TBSA or an equivalent amount of methylcellulose vehicle to groups of six- and 12-month-old 5xFAD or wild-type mice over a two-month period prevented recognition- and spatial-memory deficits in the novel-object recognition and Morris-water-maze memory tasks, respectively, and reduced the number of pyknotic and degenerated cells, Aβ plaques, and GFAP and Iba-1 immunoreactivity in the hippocampus and cortex of these mice. These findings indicate that TBSA exerts neuroprotective properties by decreasing amyloid plaque burden and neuroinflammation, thereby preventing neuronal death and preserving memory function in the 5xFAD mice.

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“…Baseline measures in the open-field (OF) test was obtained at “day 0,” treatments, and prior to OF testing began at “day 66” post-treatment (see S 1 ). The OF test was used to measure spontaneous locomotor activity, including exploratory behavior, as described previously [ 41 , 42 ]. The OF test apparatus consisted of a Plexiglas box (41 cm × 41 cm × 30 cm high; San Diego Instruments, San Diego, CA) with grids of infrared beams spaced 2.5 cm from the OF floor (used to measure horizontal activity) and 7.5 cm from the OF floor (used to measure vertical, or rearing activity) around the sides of the OF.…”

“…The novel object recognition (NOR) test is one of the most commonly used behavioral tests for investigating various aspects of learning and memory in mice. The detailed protocol was described by Leuptow and colleagues [ 41 , 43 ]. The NOR was performed in a gray polyvinyl plastic testing box (40 cm × 40 cm × 40 cm).…”

“…Morris water maze (MWM) task was used to assess spatial memory, as described previously [ 41 , 44 – 46 ]. In this task, mice are required to learn the spatial location of the hidden platform in a circular pool (180 cm in diameter and 153 cm in height) filled with water to a depth of 90 cm and kept at 20–25 °C.…”

“…Only clearly visible, large fluorescent signals were counted as Aβ plaques. A minimum of 10 serial sections, with 20–30 different fields were counted for Aβ plaques, and the mean from each group ( n = 3/group) was calculated from the counts by two researchers, who were blinded to the group identity of the specimens sampled [ 41 ].…”

Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer’s Disease

“…For immunohistochemical analyses, glial fibrillary acidic protein-GFAP and ionized calcium binding adapter molecule 1 (Iba-1) antibodies were used for labelling activated astrocytes, activated microglia respectively, whereas for labelling Aβ, 6E10 antibody was used. For the GFAP immunofluorescence protocol [ 64 ], 30-µm thick coronal sections were obtained using a cryostat (Leica; Wetzlar, Germany). Sections were rinsed three times with 1 mM PBS for 10 min each.…”