Research Article: Immunotherapy to improve cognition and reduce pathological species in an Alzheimer’s disease mouse model

Date Published: June 18, 2018

Publisher: BioMed Central

Author(s): Krystal Herline, Frances Prelli, Pankaj Mehta, Claire MacMurray, Fernando Goñi, Thomas Wisniewski.


Alzheimer’s disease (AD) is characterized by physiologically endogenous proteins amyloid beta (Aβ) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and Aβ soluble oligomers, which contain extensive β-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-β-sheet conformation antibody (aβComAb), to selectively recognize pathological Aβ and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9.

In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18–22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks.

Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p < 0.05). Furthermore, ELISA using oligomeric and monomeric Aβ showed a preferential affinity for oligomeric Aβ. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p < 0.01) and Aβ (p < 0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p < 0.01) and Barnes maze performance (p = 0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p < 0.05), and there was a trend for a reduction in soluble Aβ levels in the brain homogenates of female 3xTg-AD mice (p = 0.06). This study shows that acute treatment with an aβComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.

Partial Text

Alzheimer’s disease (AD) is a devastating neurodegenerative disease neuropathologically characterized by two physiological endogenous proteins, amyloid beta (Aβ) and tau, undergoing conformational changes and accumulating as soluble oligomers and insoluble aggregates [1–9]. These insoluble aggregates, neurofibrillary tangles (NFTs) and amyloid plaques, are now thought to be relatively inert, whereas soluble Aβ and tau oligomers are thought to be the most toxic forms [10–15]. Although there are various oligomeric species, soluble tau and Aβ oligomers are thought to share a pathological predominately β-sheet conformation [14–20].

To date, there is no effective treatment for altering the disease course of AD, a disease neuropathologically characterized by fibrillar aggregates of Aβ and hyperphosphorylated tau in the form of amyloid plaques and NFTs, respectively [5–8]. Although fibrillar Aβ associated with amyloid plaques exerts toxicity, such as generating toxic reactive oxygen species when bound to copper ions, disrupting membranes, and sequestering vital components of the proteostasis network, their overall presence in the brain has poor correlation with cognitive decline [6, 46, 50–53]. Although the presence of NFTs correlates with cognitive function better than the amyloid plaque burden, this correlation remains imperfect [6, 54–56]. Therefore, although these fibrillar aggregates do cause some local toxicity, oligomeric species are thought to be the major mediators of toxicity [8, 14, 15, 27, 54, 57–59]. Oligomers have a variety of toxic activities, such as membrane perturbation, oxidative stress, endoplasmic reticulum stress, long-term potentiation inhibition, long-term depression facilitation, channel formation, and receptor dysfunction by direct receptor binding [60–65]. Importantly, oligomeric synaptic toxic effects contribute to synapse loss, and synapse loss is the major correlate of cognitive impairment in AD [51, 66–68]. Thus, oligomers may prove to be a promising therapeutic target [16, 19, 22, 27, 69].

Overall, our studies suggest that acute treatment with an aβComAb, TWF9, can effectively improve performance in behavioral testing without needing to affect overall amyloid plaque and tau burden. Targeting both Aβ and tau concurrently may have a greater chance of future clinical therapeutic success in the setting of established AD pathology.




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