Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: A role for intraneuronal amyloid

Giménez-Llort, Lydia; Blázquez, Gloria; Cañete, Toni; Johansson, Björn; Oddo, Salvatore; Tobeña, Adolf; LaFerla, Frank M.; Fernández-Teruel, Albert

doi:10.1016/j.neubiorev.2006.07.007

Cited by 211 publications

(277 citation statements)

References 156 publications

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“…NTR -mediated degeneration of basal forebrain neurons is an early consequence of increased oligomeric A␤ levels and is tightly linked to the loss of septohippocampal function observed in both animal models and human patients with Alzheimer's disease (Klein et al, 2004;Gimenez-Llort et al, 2007). Although a significant difference in the numbers of ChAT-positive basal forebrain neurons correlated directly with A␤ 1-42 exposure, we found no obvious difference in the amount of damage in the hippocampus after injections into the CA1 region, regardless of A␤ peptide length or genotype.…”

Section: Discussionmentioning

confidence: 99%

β-Amyloid_1–42Induces Neuronal Death through the p75 Neurotrophin Receptor

Sotthibundhu¹,

Sykes²,

Fox³

et al. 2008

J. Neurosci.

208

156

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Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide A␤, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. A␤ is a ligand for the p75 neurotrophin receptor (p75 NTR ), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75 NTR is required for A␤-mediated effects. Treatment of wild-type but not p75 NTR -deficient embryonic mouse hippocampal neurons with human A␤ 1-42 peptide induced significant cell death. Furthermore, injection of A␤ 1-42 into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75 NTR -deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to A␤-induced toxicity. We also found that neuronal death correlated with A␤ 1-42 peptide-stimulated accumulation of the death-inducing p75 NTR C-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75 NTR . Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-␣ protease inhibitor-2), A␤ 1-42 -induced accumulation of the C-terminal fragment resulted from inhibition of ␥-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

β-Amyloid_1–42Induces Neuronal Death through the p75 Neurotrophin Receptor

Sotthibundhu¹,

Sykes²,

Fox³

et al. 2008

J. Neurosci.

208

156

View full text Add to dashboard Cite

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“…13 Morris water maze. Animals were tested in four paradigms in the Morris water maze (MWM) 14 consisting of one cue task for visual perceptual learning, 4 days of place task for spatial reference learning and memory followed by two probe trials for short-term (2 h) and longterm (24 h) memories. In the place learning task, mice were trained to locate a platform (7 cm diameter, 1.5 cm below the water surface, position indicated by a visible 5 × 8 cm striped flag) in a circular pool (Intex Recreation, Long Beach, CA, USA; 91 cm diameter, 40 cm height, 25°C opaque water) located in a test room with distal visual cues.…”

Section: T-mazementioning

confidence: 99%

Secreted αKlotho isoform protects against age-dependent memory deficits

et al. 2017

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αKlotho is a gene regulator of aging, increasing life expectancy when overexpressed and accelerating the development of aging phenotypes when inhibited. In mice, expression levels of the secreted isoform Klotho (s-KL) are very high in the brain, suggesting that s-KL activity may have an important role in the nervous system. Here we study the functional relevance at behavioural level of modifying s-KL levels in the aging brain. We used AAVrh10 vectors to deliver and sustained expression of s-KL in 6-and 12-monthold wild-type C57BL/6J males. This study demonstrates for we believe the first time in vivo that 6 months after a single injection of s-KL into the central nervous system, long-lasting and quantifiable enhancement of learning and memory capabilities are found. More importantly, cognitive improvement is also observable in 18-month-old mice treated once, at 12 months of age. These findings demonstrate the therapeutic potential of s-KL as a treatment for cognitive decline associated with aging.

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“…8 For unknown reasons, accumulation of insoluble fibrous material progresses from the entorhinal cortex toward regions involved in cognitive functions, particularly learning and memory. 9,10 In addition to a cholinergic deficit, which correlates with the severity of cognitive symptoms, 10 neuropsychological symptoms, such as depression and anxiety, often observed together with cognitive deficits in patients with Alzheimer disease, suggest that dysfunction of the dopaminergic sys tems might be further implicated. 9,11 Presently, curing the dis ease continues to be out of reach, and stimulating cholinergic neurotransmission remains the only successful approach that improves the cognitive state.…”

Section: J Psychiatry Neurosci 2017;42(1)mentioning

confidence: 99%

“…9,10 In addition to a cholinergic deficit, which correlates with the severity of cognitive symptoms, 10 neuropsychological symptoms, such as depression and anxiety, often observed together with cognitive deficits in patients with Alzheimer disease, suggest that dysfunction of the dopaminergic sys tems might be further implicated. 9,11 Presently, curing the dis ease continues to be out of reach, and stimulating cholinergic neurotransmission remains the only successful approach that improves the cognitive state. In this regard, cholinesterase enzymes, such as acetylcholinesterase (AChE) and butyryl cholinesterase (BuChE), are the main targets for a therapeutic approach.…”

Section: J Psychiatry Neurosci 2017;42(1)mentioning

confidence: 99%