Differential damage in the frontal cortex with aging, sporadic and familial Alzheimer's disease

Leuba, Geneviève; Vernay, André; Zimmermann, Vincent; Saini, Krishan; Kraftsik, Rudolf; Savioz, Armand

doi:10.1016/j.brainresbull.2009.06.009

Cited by 17 publications

(9 citation statements)

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“…The similar pathological characteristics of FAD in other forms of AD, despite differences in severity, support a common mechanism promoting the progression of the two forms of the disease (Lippa et al. , 1996; Leuba et al. , 2009).…”

Section: Introductionmentioning

confidence: 62%

Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice

2011

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SummaryTrafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g)1 of body weight in the drinking water. Phenylbutyric acid treatment increased secretasemediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD.

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Section: Introductionmentioning

confidence: 62%

Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice

2011

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“…We addressed this question by using brain tissues from the frontal and motor cortex of autopsied patients with AD and ALS, respectively. The frontal cortex is a severely and constantly affected region in patients with AD, where pathological features including neuronal loss, β‐amyloid deposits, and neurofibrillary tangles are prominent (Leuba et al. 2009).…”

Section: Resultsmentioning

confidence: 99%

Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity

Fujiwara

Kakita

Takahashi

2012

Journal of Neurochemistry

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Glutamate is an excitatory neurotransmitter in the CNS that plays a key role in long-term potentiation and cognitive functions such as learning and memory. However, prolonged exposure to excessive glutamate overactivates glutamate receptors and initiates neurodegenerative processes (excitotoxicity) characterized by morphological changes in the axon and the cell body (Coleman 2005;Lau and Tymianski 2010). Excitotoxicity is linked to chronic neurological disorders, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), and acute CNS insults, including ischemia. The mechanism underlying excitotoxicity is complex. Activated NMDA receptors trigger calcium influx and induce the activation of cysteine proteases, including calpain and caspases (Brorson et al. 1995;Sattler et al. 1998;Tenneti et al. 1998), and the production of nitric oxide and free radicals, both of which are detrimental to normal neuronal function (Lafon-cazal et al. 1993;Sattler et al. 1999). Despite these findings, pharmacological modulators of excitotoxicity have not provided significant neuroprotection in clinical settings (Lau and Tymianski 2010). Thus, identifying alternate mechanisms that could modulate excitotoxic effects are important for therapeutic purposes and a better understanding of neurodegenerative processes.A key molecular feature of neurodegeneration is deficits in axonal transport. Kinesins anterogradely transport cargos from the cell body to the distal axon, and the dynein-dynactin complex retrogradely transports cargos from the distal axon Received February 20, 2012 AbstractGlutamate excitotoxicity causes neuronal dysfunction and degeneration. It is implicated in chronic disorders, including Alzheimer's disease, and in acute CNS insults such as ischemia. These disorders share prominent morphological features, including axon degeneration and cell body death. However, the molecular mechanism underlying excitotoxicityinduced neurodegeneration remains poorly understood. A key molecular feature of neurodegeneration is deficits in microtubule-based cargo transport that plays a pivotal role in maintaining the balance of survival and stress signaling in the axon. We developed an excitotoxicity-induced neurodegeneration system in primary neuronal cultures. We find that excitotoxicity generates a C-terminal truncated form of p150Glued, a major component of the dynactin complex, which exacerbates axon degeneration. This p150Glued truncated form was identified in brain tissues of patients with Alzheimer's disease. Overexpression of wild-type (WT) dynein intermediate chain (DIC), a dynein component that interacts with p150Glued and links dynein and dynactin complexes, DIC (S84D) mutant, and WT p150Glued suppressed axon degeneration. These modulating effects of p150Glued and DIC on excitotoxicity-induced axon degeneration are also observed in apoptosis and cell body death. Thus, our findings identify retrograde transport proteins, p150Glued and DIC, as novel modulators of neurodegeneration induced by glutamate excitotoxici...

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“…Thus, at the same time we tested also the possibility that 6 changes in possible brain markers of AD preceeded memory decline. As parietal lobe dysfunction is an important characteristic of early AD we took tissue samples from the parietal cortex [32].…”

Section: Introductionmentioning

confidence: 99%

Increase in Alzheimer's related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat

Várga

Klausz

Domokos

et al. 2014

Brain Research Bulletin

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Alzheimer's disease (AD) is the most common form of dementia in the elderly. For more effective therapy early diagnostic markers could be beneficial. Therefore we compared one year old rats with adults and examined if changes in possible brain markers of AD preceeded memory decline. We also tested if vasopressin-deficient animals were useful model of AD as vasopressin has well known positive effect on memory and AD patient has decreased vasopressin production.We compared adult (3 month) and old (12 month), normal and vasopressin-deficient Brattleboro rats. To receive a comprehensive picture about their memory we examined their social discrimination, object discrimination and conditioned learning abilities (shuttle box).Amyloid precursor protein (APP), mitogen-activated protein kinase 1 (MAPK1), β-actin and tryptophan 2,3-dioxygenase 2 (TDO2) mRNA levels was measured by quantitative PCR.There was no difference between the memory of adult and aged groups. The vasopressin-deficient rats at both ages showed a weaker performance in the course of social and object discrimination tests and a higher escape failure during the shuttle box experiment. The brain marker mRNAs of the elder animals were higher than the levels of the adults, but the absence of vasopressin had no influence on them.Thus, the one year old rats showed elevated levels of AD-related markers, but memory deficits were observable only in vasopressin deficient animals. Vasopressin does not seem to have pathogenic role in AD. Changes in the studied markers might predict later symptoms, although further studies are required for confirmation.

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Differential damage in the frontal cortex with aging, sporadic and familial Alzheimer's disease

Cited by 17 publications

References 50 publications

Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice

Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice

Dynein and dynactin components modulate neurodegeneration induced by excitotoxicity

Increase in Alzheimer's related markers preceeds memory disturbances: Studies in vasopressin-deficient Brattleboro rat

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