Amyloid β-peptide induces apoptosis-related events in synapses and dendrites

Mattson, Mark P.; Partin, James; Begley, James G.

doi:10.1016/s0006-8993(98)00763-x

Cited by 248 publications

(150 citation statements)

References 61 publications

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“…Neuronal exposure to Aβ oligomers may have detrimental consequences, including synapse disruption, oxidative stress, altered [Ca 2+ ] i signaling, and cell death (41,42,(61)(62)(63)(64). Here we have confirmed that FAD PS enhances susceptibility to Aβ toxicity and have demonstrated a molecular mechanism through which altered [Ca 2+ ] i homeostasis plays a role in this phenotype.…”

Section: Discussionsupporting

confidence: 68%

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Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling

Müller¹,

Cárdenas²,

Mei³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in presenilins (PS) account for most early-onset familial Alzheimer's disease (FAD). Accumulating evidence suggests that disrupted Ca 2+ signaling may play a proximal role in FAD specifically, and Alzheimer's disease (AD) more generally, but its links to the pathogenesis of AD are obscure. Here we demonstrate that expression of FAD mutant PS constitutively activates the transcription factor cAMP response element binding protein (CREB) and CREB target gene expression in cultured neuronal cells and AD mouse models. Constitutive CREB activation was associated with and dependent on constitutive activation of Ca 2+ /CaM kinase kinase β and CaM kinase IV (CaMKIV). Depletion of endoplasmic reticulum Ca 2+ stores or plasma membrane phosphatidylinositolbisphosphate and pharmacologic inhibition or knockdown of the expression of the inositol trisphosphate receptor (InsP 3 R) Ca 2+ release channel each abolished FAD PS-associated constitutive CaM-KIV and CREB phosphorylation. CREB and CaMKIV phosphorylation and CREB target gene expression, including nitric oxide synthase and c-fos, were enhanced in brains of M146V-KI and 3xTg-AD mice expressing FAD mutant PS1 knocked into the mouse locus. FAD mutant PS-expressing cells demonstrated enhanced cell death and sensitivity to Aβ toxicity, which were normalized by interfering with the InsP 3 R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated InsP 3 R Ca 2+ signaling in FAD PSexpressing cells may represent a signaling pathway involved in the pathogenesis of AD.A lzheimer's disease (AD) is a fatal neurodegenerative disease associated with cognitive decline and progressive neuronal atrophy and death. Although most AD is sporadic with late onset, familial AD (FAD) is early onset due to mutations in three genes: amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2). PS1 and PS2 homologs are components of the γ-secretase APP cleavage complex. Mutations in PS are associated with AD pathogenesis, including altered γ-secretase-mediated APP cleavage and accumulation of β-amyloid (Aβ) plaques (1). The "amyloid hypothesis" proposes that Aβ accumulation triggers neurodegeneration (1). Nevertheless, whether tau and Aβ aggregations are proximal causes or symptoms of AD is a matter of debate (2). Accumulating evidence implicates disruption of intracellular calcium (Ca 2+ ) signaling as a proximal event in AD, suggesting that it could play a role in AD pathogenesis. Many neuronal functions are regulated by intracellular Ca 2+ signals, and maintenance of their dynamics is critical for proper neuronal activity (3). Several previous studies have demonstrated consistent effects of expression of FAD mutant PS on exaggerated endoplasmic reticulum (ER) Ca 2+ release in different cell types, including cortical neurons in brain slices from FAD PS1 knock-in mice (2, 4-8) suggesting that it is a fundamental alteration in FAD. Exaggerated ER Ca 2+ release may be caused by lack of a putative ER membrane Ca 2+ leak function of PS (9) or by activation of...

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Section: Discussionsupporting

confidence: 68%

“…Previous studies have found that the expression of FAD PS enhances apoptosis, with altered Ca 2+ homeostasis and oxidative stress proposed to play important roles (41,42), but the molecular mechanisms have remained unclear. We also observed that FAD PS enhanced basal levels of cell death.…”

Section: Discussionmentioning

confidence: 99%

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling

Müller¹,

Cárdenas²,

Mei³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…They demonstrated that A␤ and A␤ [25][26][27][28][29][30][31][32][33][34][35] induce apoptosis through caspase-dependent pathways. [41][42][43][44][45][46][47] In vivo, 1 week after A␤ [25][26][27][28][29][30][31][32][33][34][35] , an increase in caspase-3 activity in the hippocampus of rats 9 and increases in levels of pro-caspases 9, 12, and 3 in the hippocampus of mice 11 were observed. In the present study, we observed increases in pro-and cleaved forms for caspase-9 (mitochondrial stress marker) and caspase-12 (endoplasmic reticulum stress marker) in all structures except the hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

Zussy

Brureau

Delair

et al. 2011

The American Journal of Pathology

121

129

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Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid ␤ protein (A␤) formed by pathological processing of the A␤ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated A␤ fragment 25-35 (A␤ 25-35 ) in rats. Using a combined biochemical, behavioral, and morphological approach, we analyzed the peptide effects after 1, 2, and 3 weeks in the hippocampus, cortex, amygdala, and hypothalamus. The scrambled A␤ 25-35 peptide was used as negative control. The aggregated forms of A␤ peptides were first characterized using electron microscopy, infrared spectroscopy, and Congo Red staining. Intracerebroventricular injection of A␤ 25-35 decreased body weight, induced short-and long-term memory impairments, increased endocrine stress, cerebral oxidative and cellular stress, neuroinflammation, and neuroprotective reactions, and modified endogenous amyloid processing, with specific time-course and regional responses. Moreover, A␤ 25-35 , the presence of which was shown in the different brain structures and over 3 weeks, provoked a rapid glial activation, acetylcholine homeostasis perturbation, and hippocampal morphological alterations. Alzheimer's disease (AD) is a chronic neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss in brain areas responsible for learning and memory impairments. 1 The major component of senile plaques is an amyloid ␤ protein (A␤) derived from amyloid precursor protein (APP). Genetic, cell biological, and postmortem studies on AD brain, together with A␤ neurotoxicity findings, gave rise to the amyloid cascade hypothesis to explain A␤-associated neurodegenerative processes. 2 In normal healthy individuals, A␤ peptides are present only in small quantities, as soluble monomers that circulate in cerebrospinal fluid and blood. In AD patients, A␤ peptides, which vary in length from 40 to 43 amino acids, accumulate as insoluble fibrillar deposits. 3 When cultured rat hippocampal neurons are exposed to aggregated A␤ peptides, their neurites adopt a dystrophic appearance and become comparable to those observed surrounding and infiltrating senile plaques. This observation suggested that A␤ is responsible for the neuritic abnormalities in AD pathology. 4 Structure-activity studies revealed that peptides containing the highly hydrophobic 25-35 region formed stable aggregates and mediated neuronal death by necrosis or apoptosis. 5,6,7 The truncated A␤ 25-35 fragment includes extracellular and intramembrane residues that have been reported to represent an active region of A␤. 8

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“…Los efectos del βA han sido ampliamente estudiados, suponen desde la inducción de muerte neuronal apoptótica (Estus et al, 1997), al desencadenamiento de un programa apoptótico parcial que da como resultado cambios en las neuritas (Mattson et al, 1998). Estos efectos neurotóxicos están principalmente mediados a través de la producción de glutamato, que es disparada por los diferentes receptores de NMDA, y se correlaciona con la activación de caspasas y la consecuente apoptosis neuronal (Erdmann et al, 2006).…”

Section: Discussionunclassified

VIH-1 Y Alzheimer: ¿una conexión real?

González

Álvarez

2012

Revista Complutense De Ciencias Veterinarias

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RESUMENLa infección por el virus de inmunodeficiencia humana (VIH) causa alteraciones neurológicas que son más graves y frecuentes como consecuenia del envejecimieno de la población. Este daño se asocia a la disfunción neuronal, que patológicamente se caracteriza como una pérdida de sinapsis, acortamiento de neuritas, anormalidades dendríticas, así comon pérdida neuronal.A este respecto, varios estudios han observado un aumento significativo de placas amiloides en cerebros de individuos infectados por el VIH en comparación con controles sanos, así como en individuos VIH positivos que habían estado expuestos a la terapia antirretroviral. En este trabajo se ha investigado el efecto de la combinación del péptido β-amiloide e infección por VIH-1 en diferentes células del sistema nervioso. El pretratamiento de las células gliales y neuronales provoca un incremento en la replicación viral, así como el tratamiento combinado virus y formas de oligómeros y fibrillas producen un incremento en las especies reactivas de oxígeno y de la forma activa de la enzima proapoptótica caspasa-3, en astrocitos. Lo que podría traducirse como un incremento de neurotoxicidad y depositos de β-amiloide en el cerebro infectado. Palabras clave:VIH-1, beta-amiloide, neuropatogénesis, especies reactivas de oxígeno, caspasa-3 ABSTRACTInfection by human immunodeficiency virus (HIV) promotes neurological alterations which are more severe and frequents, due to the aging of the population. This dementia is associated

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Amyloid β-peptide induces apoptosis-related events in synapses and dendrites

Cited by 248 publications

References 61 publications

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

VIH-1 Y Alzheimer: ¿una conexión real?

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Amyloid β-peptide induces apoptosis-related events in synapses and dendrites

Cited by 248 publications

References 61 publications

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3 R) Ca 2+ signaling

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3 R) Ca 2+ signaling

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

VIH-1 Y Alzheimer: ¿una conexión real?

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Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling

Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP ₃ R) Ca ²⁺ signaling