Article

Neuronal IGF-1 resistance reduces A accumulation and protects against premature death in a model of Alzheimer's disease

Department of Internal Medicine II, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
The FASEB Journal (Impact Factor: 5.04). 07/2009; 23(10):3315-24. DOI: 10.1096/fj.09-132043
Source: PubMed

ABSTRACT

Alzheimer's disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP(SW), Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R(-/-)), or neuronal insulin receptor (nIR(-/-)), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays beta-amyloid (Abeta) accumulation. Analysis of APP metabolism suggested that delayed Abeta accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R(-/-)Tg2576 mice were protected from premature death in the presence of decreased Abeta accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.

  • Source
    • "The role of IGF-1Rs in neurodegenerative disorders has remained highly controversial. While IGF-1 injections promote Ab clearance (Carro et al., 2002) and blockade of IGF-1Rs in the choroid plexus exacerbate AD-like pathology, genetic reduction in the IGF-1R protects mice from Ab-associated proteotoxicity (Cohen et al., 2009;Freude et al., 2009). Our study suggests that IGF-1R overexpression, observed in the hippocampus of APP/PS1 mice (Zhang et al., 2013), triggers presynaptic dysfunctions at the early stage, preceding synaptic loss and Ab aggregation . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer’s disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca2+ transients, while promoting spontaneous transmission and resting Ca2+ level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca2+ buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer’s disease.
    Full-text · Article · Jan 2016 · Neuron
  • Source
    • "This common temporal emergence pattern defines aging as the major risk factor for the development of neurodegeneration (Amaducci & Tesco, 1994) and suggests that aging-associated decline in the efficiency of protein quality control mechanisms underlies the etiology of these illnesses. This theme is strongly supported by the finding that the alteration of aging protects model worms (Morley et al, 2002; Cohen et al, 2006) and mice (Cohen et al, 2009; Freude et al, 2009) from proteotoxicity. The detailed molecular mechanisms that lead to the development of AD, the most prevalent human neurodegenerative disorder, are largely obscure. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mito-chondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
    Full-text · Article · Oct 2015 · The EMBO Journal
  • Source
    • "IGF1 and IGF2 are thought to play a role in the pathogenesis of sporadic AD [51]. Furthermore, IGF1 has been linked to neuroprotection [29] [30] although there is also evidence that it may promote amyloid deposition [52] [53]. Importantly, the bioavailability and actions of IGF1 are influenced by IGFBPs [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
    Full-text · Article · Oct 2014 · Journal of Alzheimer's disease: JAD
Show more