Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Bartus, Raymond T.; Dean, Reginald L.

doi:10.1007/s00213-008-1365-7

Cited by 32 publications

(24 citation statements)

References 148 publications

(159 reference statements)

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“…Importantly, a loss of cholinergic neuromodulation is thought to be at least partially responsible for memory impairment in neurodegenerative diseases such as Alzheimer's disease (Bartus, 2000;Bartus and Dean, 2009). However, the extent to which cholinergic deficits can account for impaired memory in dementia has been questioned based on the failure of selective lesions of cortical cholinergic input to produce substantial impairment on many tests of memory in animals (Voytko et al, 1994;Baxter and Gallagher, 1997;Baxter and Murg, 2002).…”

Section: Introductionmentioning

confidence: 99%

Medial septal cholinergic neurons are necessary for context‐place memory but not episodic‐like memory

et al. 2011

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Loss of cholinergic cortical input is associated with diseases in which episodic memory impairment is a prominent feature, but the degree to which this neurochemical lesion can account for memory impairment in humans with neurodegenerative diseases remains unclear. Removal of cholinergic input to hippocampus impairs some of its functions in memory, perhaps by reducing the plasticity of information representation within the hippocampus, but the role of cholinergic hippocampal input in episodic-like memories has not been investigated. To address this question, we tested rats with selective lesions of basal forebrain neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), which contains hippocampal-projecting cholinergic neurons, on a task of integrated memory for objects, places, and contexts ("what-where-which" memory). This task serves as a rodent model of human episodic memory (episodic-like memory) and is sensitive to damage to the hippocampal system. Rats with lesions of cholinergic MS/VDB neurons performed as well on the what-where-which task as controls, but were impaired in a task that simply required them to associate places with contexts ("where-which" memory). Thus, episodic-like memories that rely on the hippocampus do not require cholinergic neuromodulation to be formed. Nevertheless, some more specific aspects of where-which memory, which may be more dependent on the plasticity of hippocampal spatial representations, require acetylcholine. These results suggest that cholinergic projections to hippocampus are not necessary for episodic memory and, furthermore, that hippocampal spatial representations may be to some extent dissociable from episodic memory function.

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Section: Introductionmentioning

confidence: 99%

Medial septal cholinergic neurons are necessary for context‐place memory but not episodic‐like memory

et al. 2011

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“…Additionally, we demonstrate that NRTN can produce the desired and predicted neurotrophic response (both cellular hypertrophy and induction of pERK in the targeted neurons), substantially expanding the age-related data initially published with AAV2-NRTN in 3 aged monkeys [44] and AA V2-NGF with aged rats [42]. Thus, these data further support the use of AAV-mediated gene transfer for age-related neurodegenerative diseases, for it has been argued long ago that aged animals can provide important information as models for age-related neurodegenerative diseases [56][57][58] and indeed aged animals have since been used as models to address certain translational questions for both AD [35,37,[59][60][61] and PD [62].…”

Section: Discussionmentioning

confidence: 53%

“…For AD, cholinesterase inhibitors remain the mainstay of treatment for the cognitive deficits, but their effects are modest and occur only in an unpredictable portion of the AD population, particularly in the earlier stages of the disease [35,37]. Significant, dose-limiting side effects dampen what might otherwise be possible from enhancing cholinergic neuronal function, but given the ubiquitous status of neurons using acetylcholine throughout the brain and body, that scenario is unlikely to improve (and has not in the decades following the initial approval of this class of drugs).…”

Section: Discussionmentioning

confidence: 99%

“…clinicaltrials.gov; identifier NCT00876863). NGF has been shown to exert robust neurotrophic effects on basal forebrain cholinergic neurons, whose loss of function has been linked to the cognitive deficits in early stage disease [35][36][37]. NRTN has been shown to exert robust neurotrophic effects on nigrostriatal dopamine neurons, the loss of which has been linked to the major motor deficits characteristic of Parkinson's disease [38].…”

Section: Introductionmentioning

confidence: 99%

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Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases

Herzog¹,

Bishop²,

Brown³

et al. 2011

Drug Deliv. and Transl. Res.

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Efforts to develop neurotrophic factors to restore function and protect dying neurons in chronic neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD) have been attempted for decades. Despite abundant data establishing nonclinical proof-of-concept, significant delivery issues have precluded the successful translation of this concept to the clinic. The development of AAV2 viral vectors to deliver therapeutic genes has emerged as a safe and effective means to achieve sustained, long-term, targeted, bioactive protein expression. Thus, it potentially offers a practical means to solve those long-standing delivery/translational issues associated with neurotrophic factors. Data are presented for two AAV2 viral vector constructs expressing one of two different neurotrophic factors: nerve growth factor (NGF) and neurturin (NRTN). One (AAV2-NGF; aka CERE-110) is being developed as a treatment to improve the function and delay further degeneration of cholinergic neurons in the nucleus basalis of Meynert, the degeneration of which has been linked to cognitive deficits in AD. The other (AAV2-NRTN; aka CERE-120) is similarly being developed to treat the degenerating nigrostriatal dopamine neurons and major motor deficits in PD. The data presented here demonstrate: (1) 2-year, targeted, bioactive-protein in monkeys, (2) persistent, bioactive-protein throughout the life-span of the rat, and (3) accurately targeted bioactive-protein in aged rats, with (4) no safety issues or antibodies to the protein detected. They also provide empirical guidance to establish parameters for human dosing and collectively support the idea that gene transfer may overcome key delivery obstacles that have precluded successful translation of neurotrophic factors to the clinic. More specifically, they also enabled the AAV-NGF and AAV-NRTN programs to advance into ongoing multi-center, double-blind clinical trials in AD and PD patients.

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“…The receptor for AGEs (RAGE), a multi-ligand receptor of the immunoglobulin superfamily of cell surface molecules (5), possesses a cell surface binding site for Aβ peptides (4) and is expressed at higher levels when stimulated by excessive levels of Aβ (6). RAGE has been extensively studied for its roles in the migration and differentiation of neuronal cells during development, the perturbation of neuronal cells by Aβ and the inflammatory response (3,7).…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic role of advanced glycation end-products in PC12 cells treated with β-amyloid peptide

Yan

Han

2013

Molecular Medicine Reports

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Abstract. Alzheimer's disease (AD) is the most common type of dementia afflicting the elderly. Recent studies have increasingly suggested that a high concentration of advanced glycation end products (AGEs) may be important in AD pathogenesis. However, the mechanisms and pathways involved remain unknown. The aim of this study was to explore whether the mechanism of the effect of AGEs on Aβ-PC12 cells [PC12 cells treated with β-amyloid (Aβ) peptide] was associated with oxidative stress; and to study whether inhibiting the activity of the receptor for AGE (RAGE) attenuated the toxic effect of AGEs and Aβ on PC12 cells. Several PC12 cells were pretreated with Aβ, and were then treated with different concentrations of AGEs. Other PC12 cells were treated with trypsin, a pancreatic protein enzyme and an inhibitor of RAGE, and were then treated with Aβ and AGEs. Apoptosis was measured by flow cytometry (FCM) and cell viability was measured by MTT assay. RAGE and nuclear factor-κB (NF-κB) were measured by reverse transcription-polymerase chain reaction (RT-PCR) assay. With an increase in AGE concentration, the viability of Aβ-PC12 cells treated with AGEs decreased. However, the Aβ-PC12 cell viability was greater in the trypsin group than in the non-trypsin group. Cell apoptosis rates and mRNA expression of RAGE and NF-κB in Aβ-PC12 cells treated with AGEs were significantly higher than in the Aβ-PC12 cells. AGEs and Aβ were neurotoxic, and RAGE triggered the neural cytotoxic role of AGEs in Aβ-PC12 cells. The molecular mechanisms may be connected with the expression of NF-κB and apoptosis mediated by RAGE. Inhibiting the activity of RAGE may mitigate the toxic effect of AGEs and Aβ on neural cells.

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Pharmaceutical treatment for cognitive deficits in Alzheimer’s disease and other neurodegenerative conditions: exploring new territory using traditional tools and established maps

Cited by 32 publications

References 148 publications

Medial septal cholinergic neurons are necessary for context‐place memory but not episodic‐like memory

Medial septal cholinergic neurons are necessary for context‐place memory but not episodic‐like memory

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases

Cytotoxic role of advanced glycation end-products in PC12 cells treated with β-amyloid peptide

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