Oral Treatment with a γ-Secretase Inhibitor Improves Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

Abstract

The ␤-amyloid peptide (A␤) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of A␤ on the brain, transgenic mouse models have been developed that express high levels of A␤. These mice show some features of AD, including amyloid plaques and mild cognitive impairment, but not others such as progressive neurodegeneration. We investigated the age-dependent effects of A␤ on synaptic physiology in Tg2576 mice that express human A␤. We report that both basal synaptic activity and long-term potentiation (LTP), as measured in the CA1 region of the hippocampus, were compromised by 7 months of age before plaque deposition. Despite a persistent increase in A␤ levels with age, LTP recovered in 14-month-old mice, with no further loss of basal activity compared with activity measured in 7-month-old mice. Previous work has shown that inhibitors of ␥-secretase, an enzyme critical for A␤ synthesis, can significantly reduce A␤ production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available ␥-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of A␤ reduction. These results indicate that recovery from A␤-mediated synaptotoxicity can occur rapidly with A␤-lowering therapies. These findings highlight some of the strengths and limitations of using A␤-overexpressing mouse models for Alzheimer's drug discovery.Alzheimer's disease (AD) is characterized clinically by progressive loss of memory and the pathological accumulation of neurofibrillary tangles and amyloid plaques in the brain. Tangles are composed of a fibrillized form of the microtubulebinding protein tau. Amyloid lesions contain ␤-amyloid peptide (A␤) produced endogenously by the proteolytic cleavage of the amyloid precursor protein (APP) by ␤-secretase and ␥-secretase (Wolfe, 2006;Cole and Vassar, 2008). Mutations near the cleavage sites of APP cause early onset AD as do variants in the ␥-secretase subunit presenilin 1. These mutations typically elevate A␤ production or increase A␤42/40 ratios, which result in a more aggregation-prone form of the peptide. Essential to developing disease-modifying therapies for AD is the identification and characterization of relevant preclinical animal models.Transgenic mice that express human disease variants of APP or presenilin 1 develop amyloid plaques, memory impairment, deficits in synaptic function, gliosis, and dystrophic neurites (Ashe, 2006; Gotz and Ittner, 2008;Morrissette et al., 2009). However, despite high levels of A␤ expression, these mice typically lack the overt tau pathology, neurodegeneration, and show only modest cognitive impairment. The full value of these preclinical models of Alzheimer's disease requires an explanation for the incomplete pathology. Tg2576 mice that express the APPsw mutation (K770N, M671L) have been widely studied (Hsiao et al., 1996;Ashe, 2006) as a model for pl...

Long-lasting efficacy of the cognitive enhancer Cytotoxic Necrotizing Factor 1

“…Object recognition is impaired in animal models of Alzheimer's disease (AD) (Taglialatela et al, 2009) and ID, such as Down syndrome (Belichenko et al, 2009;Fernandez et al, 2007) and Fragile X syndrome (Ventura et al, 2004). In these models, reduced LTP has been reported (Fernandez et al, 2007;Lauterborn et al, 2007;Townsend et al, 2010) along with derangement of Rho signaling (MendozaNaranjo et al, 2007;Petratos et al, 2008) and/or alterations of the dendritic tree/spines (Benavides-Piccione et al, 2004;Comery et al, 1997;Perez-Cruz et al, 2011). Experimental approaches based on Rho modulation have shown pre-clinical efficacy in animal models of ID (Bongmba et al, 2011;De Filippis et al, 2011).…”

A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

“…Several studies have demonstrated that synaptic plasticity is correlated with learning and memory (Kandel, 2001;VanGuilder et al, 2011). Therefore, we examined whether improved cognitive performance following BTA-EG 4 treatment is associated with altered synaptic function and plasticity.…”

“…This presents an interesting point by implying that creating new synapses may benefit cognitive function not by enhancing LTP at individual synapses, but by allowing more synaptic contact points to form along the dendrite for potential information storage. It is of interest to note that some of the APP transgenic AD mouse models display larger LTP in younger age (Marchetti and Marie, 2011;Wang et al, 2012). It would be of interest to know whether BTA-EG 4 treatment in these young AD mouse models would show beneficial effects.…”

“…These therapies were also able to prevent or improve memory deficits in AD mice. Furthermore, ␥-secretase and HDAC inhibitors increase LTP, increase dendritic spine density, and improve cognitive performance (Townsend et al, 2010;Haettig et al, 2011). In contrast to these results, we found that while BTA-EG 4 had positive effects on cognitive performance and dendritic spine density, it did so without a correlated increase in the magnitude of LTP at both SC and TA inputs to CA1 (Fig.…”

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…100 When another mouse model, Tg2576 mice, which also expressed mutant human APP and had an increased amyloid β burden, were fed a γ-secretase inhibitor to reduce amyloid β levels, there was a profound restoration of impaired long-term potentiation, confirming that amyloid β does affect synaptic plasticity. 101 To understand the mechanisms whereby amyloid β can influence synaptic plasticity, many groups have examined the effects of amyloid β peptide derived from different sources in organotypic hippocampal slice preparations. These studies have shown that naturally occurring amyloid β peptides obtained from spinal fluid 102 or directly from brains of individ uals with Alzheimer disease 103 and naturally secreted amyloid β oligos from cultured cells can affect long-term potentiation and synaptic density.…”