Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

Granic, Ivica; Nyakas, Csaba; Luiten, P.G.M.; Eisel, Ulrich; Halmy, L; Groß, Gerhard; Möller, Achim; Nimmrich, Volker

doi:10.1016/j.neuropharm.2010.07.013

Cited by 33 publications

(27 citation statements)

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“…The main phenolic component of olive oil, oleuropein, has been shown to possess antioxidant [262] , anti-inflammatory [263] and hypolipidemic activities [264] . Small molecules (NQTrp, ClNQTrp, coumarin, furosemide, D737) that inhibit Aβ aggregation [265,266] or remodel toxic soluble oligomers of Aβ [267] inhibit oligomer formation [268][269][270][271][272][273][274] (Table 3).…”

Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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Section: Small Molecule Inhibitorsmentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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“…In a nucleus basalis lesion model in rats, which mimics the cholinergic degeneration in AD, verapamil prevented behavioural deficits that occur as a result of the lesion (Popović et al, 1997). Blocking calcium-activated proteases further downstream prevented Aβ oligomer-induced nucleus basalis lesions, degeneration of cholinergic fibres as well as associated behavioural deficits (Granic et al, 2010).It is now well accepted that Aβ is detrimental to synaptic plasticity (Selkoe, 2008). Long-term potentiation (LTP) is a correlate for learning and memory (Bliss and Collingridge, 1993), and it is thought that LTP-like processes are disturbed in AD.…”

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confidence: 94%

Calcium channel blockers and dementia

Nimmrich

Eckert

2013

British J Pharmacology

133

104

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Degenerative dementia is mainly caused by Alzheimer's disease and/or cerebrovascular abnormalities. Disturbance of the intracellular calcium homeostasis is central to the pathophysiology of neurodegeneration. In Alzheimer's disease, enhanced calcium load may be brought about by extracellular accumulation of amyloid-β. Recent studies suggest that soluble forms facilitate influx through calcium-conducting ion channels in the plasma membrane, leading to excitotoxic neurodegeneration. Calcium channel blockade attenuates amyloid-β-induced neuronal decline in vitro and is neuroprotective in animal models. Vascular dementia, on the other hand, is caused by cerebral hypoperfusion and may benefit from calcium channel blockade due to relaxation of the cerebral vasculature. Several calcium channel blockers have been tested in clinical trials of dementia and the outcome is heterogeneous. Nimodipine as well as nilvadipine prevent cognitive decline in some trials, whereas other calcium channel blockers failed. In trials with a positive outcome, BP reduction did not seem to play a role in preventing dementia, indicating a direct protecting effect on neurons. An optimization of calcium channel blockers for the treatment of dementia may involve an increase of selectivity for presynaptic calcium channels and an improvement of the affinity to the inactivated state. Novel low molecular weight compounds suitable for proof-of-concept studies are now available. AbbreviationsAβ, amyloid-β; AD, Alzheimer's disease; APP, amyloid precursor protein; LTP, long-term potentiation; VaD, vascular dementia; VGCC, voltage-gated calcium channel IntroductionDementia affects 7% of the population over the age of 65, and then progressively increases with age Rocca et al., 1991). Alzheimer's disease (AD) is the leading cause of dementia, followed by vascular dementia (VaD). AD is characterized by three neuropathological hallmarks: extracellular aggregates of amyloid-β (Aβ) peptide (amyloid plaques), neurofibrillary tangles and synaptic loss (Bell and Cuello, 2006). According to the amyloid cascade hypothesis, overproduction of the hydrophobic peptide Aβ 1-42 is the basis for AD pathology (Hardy and Higgins, 1992).Aggregation of Aβ 1-42 is thought to occur in several steps via fibrils, which are finally deposited as amyloid plaques. It was suggested that an alternative pathway leads to the generation of stable oligomeric aggregates, Aβ oligomers (Gellermann et al., 2008;Yu et al., 2009b), which are considered to mediate the toxic Aβ effects (Hardy and Selkoe, 2002). Different forms of Aβ oligomers can be generated synthetically (e.g. Stine et al., 2003; Barghorn et al., 2005) or are harvested from cell lines (Walsh et al., 2002). These preparations were tested in vitro and in animal models, and the results lead to the generally accepted view that Aβ oligomers specifically disturb synaptic function . Constant impairment of neurotransmission leads to a retraction of synapses, which is then evident in the autopsy of AD brains (for a review, see Nimmrich a...

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“…The accumulation of Ab protein aggregates causes the degeneration of cholinergic neurons in the hippocampus and the nucleus basalis of Meynert, which results in cholinergic deficiency and synapse loss in the AD brain (Terry et al, 1991;van der Zee and Luiten, 1999). The loss of the cholinergic neuronal population in AD patients leads to an impairment of higher cortical functions, which is directly related to the progressive deterioration of memory, attention, and cognitive processes (Chopra et al, 2011;Granic et al, 2010). Indeed, a reduction in the acetylcholine concentration in the cholinergic synaptic cleft was observed in the AD brain (Mufson et al, 2008;Pakaski and Kalman, 2008).…”

Section: Introductionmentioning

confidence: 99%