Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid β-Peptide-induced Neuronal Apoptosis

Abstract

A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid ␤-peptide (A␤) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble A␤ remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. Microtubules are polymers of ␣-and ␤-tubulin dimers that mediate many functions in neurons, including organelle transport and cell shape establishment and maintenance as well as axonal elongation and growth cone steering in neurons. The polymerization, stabilization, and dynamic properties of microtubules are influenced by interactions with microtubule-associated proteins (MAPs).3 Members of this protein family are classified by size: high molecular mass proteins (MAP1A, MAP1B, MAP2a, and MAP2b) and intermediate molecular mass proteins (MAP2c, MAP2d, and tau) (1-3). Numerous studies have shown that neuronal apoptotic cell death involves alterations of the microtubule network consequent to calpain and effector caspase activation (4, 5). These calcium-dependent proteases are responsible for the degradation and turnover of a broad repertoire of MAP substrates, some of which they share, such as ␣II-spectrin and tau, and some of which are specific, as is the case of calpain-degraded MAP1B and MAP2.Intraneuronal neurofibrillary tangles (NFTs) are one of the histopathological hallmarks in brains of patients diagnosed with Alzheimer disease (AD), a progressive dementia that manifests primarily as a profound inability to form new memories. These NFTs are composed of hyperphosphorylated tau organized into paired helical filaments (PHFs) (6). In addition, AD is also associated with the presence of extracellular senile plaques (7) formed as a consequence of the gradual accumulation and aggregation of the amyloid ␤-peptide (A␤) into fibrils (8). Despite evidence that A␤ represents a key factor in AD (9), the nature of the toxic form of A␤ involved early in AD pathology remains to be determined. The issue of which pool (soluble or aggregated) of A␤ in brain is more deleterious in the early stages of AD is still controversial (10). However, clinicopathological hallmarks of AD correlate far better with the soluble pool of A␤ (11,12). Moreover, several studies in transgenic mice have indicated that specific cognitive deficits, neurodegeneration, and synaptic loss might occur before any histologically detectable formation of senile plaques (13,14). So, in reports from our group (15-18) and others (19,20), attention has been paid to the soluble oligomeric forms of A␤ as the principal mediators of neurodegeneration in the early stages of AD development (10, 19 -23).Increasing evidence suggests that the selective neuronal cell death in AD involves activation of caspa...

Protective effects of tetramethylpyrazine on rat retinal cell cultures

“…In this case, about 70% of retinal neurons that had very low levels of MAP-2 following siRNA transfection were detected as TUNEL-positive due to a sublethal exposure to ROS. This observation is in agreement with previous studies that demonstrated reduction of MAP-2 in degenerating neurons induced by ROS-generating agents in vitro or ischemia in vivo (Wang et al, 2001;Fifre et al, 2006). Although the discrepancy of glial support might indirectly intervene neuronal surviving in the presence of TMP, retaining of the neuronal specific MAP-2 protein in neuronal soma by TMP appeared to increase specifically the resistance of neurons to attacks.…”

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

“…As a result of this work, it has been shown that dynamin 1 was significantly reduced not only in the hippocampus of an AD mouse model and in cultured hippocampal neurons treated with Aβ but also in the brain of AD patients (Yao et al 2003;Kelly et al 2005;Kelly and Ferreira 2006). The mechanisms leading to this dynamin 1 depletion seem to involve calpain, a protease system that is active in AD (Tsuji et al 1998;Lee et al 2000;Battaglia et al 2003;Tomizawa et al 2003;Chen and Fernandez 2005;Demuro et al 2005;Gong et al 2005;Kelly et al 2005;Fifre et al 2006;Kelly and Ferreira 2006). Furthermore, we have reported that this Aβ-mediated dynamin 1 degradation was the result of calpain activation induced by the sustained calcium influx mediated by N-methyl-D-aspartate (NMDA) receptors in hippocampal neurons (Kelly and Ferreira 2006).…”

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

“…MAP-2 is a microtubule-associated protein that has been shown to be decreased in some models of neurodegeneration and AD. 33,34 In particular, it was reported that rats fed with a high-fat diet (soybean oil and cholesterol supplemented, no fructose) for 8 weeks present a diminished staining of MAP-2 in the hippocampus, and that this reduction is correlated with memory errors. 16 Microtubule-associated protein 2 modifies and controls microtubule assembly and spacing within dendrites.…”