Increased synthesis and accumulation of heat shock 70 proteins in Alzheimer's disease

Perez, N.; Sugar, Joel; Charya, S.; Johnson, G.; Merril, Carl R.; Bierer, Linda M.; Perl, Daniel P.; Haroutunian, Vahram; Wallace, William

doi:10.1016/0169-328x(91)90033-t

Cited by 125 publications

(68 citation statements)

References 26 publications

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“…Our data demonstrates an upregulation of Hsp70 in response to intraneuronal A␤42 expression in a dose-dependent manner. This finding supports previous observations of increased accumulation of Hsp70 in AD brains (Hamos et al, 1991;Perez et al, 1991). Thus, we hypothesized that an imbalance be- tween the neuronal Hsp capacity and the toxic accumulation of A␤ may be responsible for the observed neuron death.…”

Section: Discussionsupporting

confidence: 91%

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Magrané

Smith²,

Walsh³

et al. 2004

J. Neurosci.

228

187

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Intracellular ␤-amyloid 42 (A␤42) accumulation is increasingly recognized as an early event in the pathogenesis of Alzheimer's disease (AD). We have developed a doxycycline-inducible adenoviral-based system that directs intracellular A␤42 expression and accumulation into the endoplasmic reticulum of primary neuronal cultures in a regulated manner. A␤42 exhibited a perinuclear distribution in cell bodies and an association with vesicular compartments. Virally expressed intracellular A␤42 was toxic to neuronal cultures 24 hr after induction in a dose-dependent manner. A␤42 expression prompted the rapid induction of stress-inducible Hsp70 protein in neurons, and virally mediated Hsp70 overexpression rescued neurons from the toxic effects of intracellular A␤ accumulation. Together, these results implicate the cellular stress response as a possible modulator of A␤-induced toxicity in neuronal cultures.

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Section: Discussionsupporting

confidence: 91%

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Magrané

Smith²,

Walsh³

et al. 2004

J. Neurosci.

228

187

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“…Early studies using immunohistochemistry and immunoblotting suggested that expression of both HSP70-class (34,35) and ␣B-crystallin-related proteins (36,37) was increased in AD brains, and both classes of proteins were associated with senile plaques. A more recent study using two-dimensional PAGE coupled with mass spectrometry confirmed the increased expression of ␣B-crystallin but found that specific HSP70-class proteins may be increased (HSPA4), decreased (HSPA8), or unchanged (HSPA1B, HSPA5) in specific regions of AD brains (38).…”

Section: Discussionmentioning

confidence: 99%

Interaction of intracellular β amyloid peptide with chaperone proteins

Fonte

Kapulkin²,

Taft³

et al. 2002

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

199

151

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Expression of the human β amyloid peptide (Aβ) in transgenic Caenorhabditis elegans animals can lead to the formation of intracellular immunoreactive deposits as well as the formation of intracellular amyloid. We have used this model to identify proteins that interact with intracellular Aβ in vivo . Mass spectrometry analysis of proteins that specifically coimmunoprecipitate with Aβ has identified six likely chaperone proteins: two members of the HSP70 family, three αB-crystallin-related small heat shock proteins (HSP-16s), and a putative ortholog of a mammalian small glutamine-rich tetratricopeptide repeat-containing protein proposed to regulate HSP70 function. Quantitative reverse transcription–PCR analysis shows that the small heat shock proteins are also transcriptionally induced by Aβ expression. Immunohistochemistry demonstrates that HSP-16 protein closely colocalizes with intracellular Aβ in this model. Transgenic animals expressing a nonaggregating Aβ variant, a single-chain Aβ dimer, show an altered pattern of coimmunoprecipitating proteins and an altered cellular distribution of HSP-16. Double-stranded RNA inhibition of R05F9.10, the putative C. elegans ortholog of the human small glutamine-rich tetratricopeptide-repeat-containing protein (SGT), results in suppression of toxicity associated with Aβ expression. These results suggest that chaperone function can play a role in modulating intracellular Aβ metabolism and toxicity.

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“…In a rat model of Parkinson's disease, Hsp104 was found to be similarly efficient (Lo Bianco et al 2008). An increased level of expression of small Hsps and Hsp70 in the brain of AD patients has been reported in a number of studies (Perez et al 1991;Muchowski and Wacker 2005). Several studies suggest that expression of Hsps could suppress the progression of AD (Magrané et al 2004;Muchowski and Wacker 2005;Evans et al 2006).…”

Section: Introductionmentioning

confidence: 92%

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

Tóth

Szegedi

Varga

et al. 2013

Cell Stress and Chaperones

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Hsp27 belongs to the small heat shock protein family, which are ATP-independent chaperones. The most important function of Hsp27 is based on its ability to bind non-native proteins and inhibit the aggregation of incorrectly folded proteins maintaining them in a refolding-competent state. Additionally, it has anti-apoptotic and antioxidant activities. To study the effect of Hsp27 on memory and synaptic functions, amyloid-β (Aβ) accumulation, and neurodegeneration, we generated transgenic mice overexpressing human Hsp27 protein and crossed with APPswe/PS1dE9 mouse strain, a mouse model of Alzheimer's disease (AD). Using different behavioral tests, we found that spatial learning was impaired in AD model mice and was rescued by Hsp27 overexpression. Electrophysiological recordings have revealed that excitability of neurons was significantly increased, and long-term potentiation (LTP) was impaired in AD model mice, whereas they were normalized in Hsp27 overexpressing AD model mice. Using anti-amyloid antibody, we counted significantly less amyloid plaques in the brain of APPswe/PS1dE9/Hsp27 animals compared to AD model mice. These results suggest that overexpression of Hsp27 protein might ameliorate certain symptoms of AD.

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Increased synthesis and accumulation of heat shock 70 proteins in Alzheimer's disease

Cited by 125 publications

References 26 publications

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Heat Shock Protein 70 Participates in the Neuroprotective Response to Intracellularly Expressed β-Amyloid in Neurons

Interaction of intracellular β amyloid peptide with chaperone proteins

Overexpression of Hsp27 ameliorates symptoms of Alzheimer's disease in APP/PS1 mice

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