Amyloid, the presenilins and Alzheimer's disease

Hardy, John

doi:10.1016/s0166-2236(96)01030-2

Cited by 1,288 publications

(840 citation statements)

References 34 publications

Supporting

Mentioning

810

Contrasting

Unclassified

Order By: Relevance

Section: Introductionmentioning

confidence: 99%

“…Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

show abstract

“…In the amyloidogenic pathway, APP cleavage leads to the production of A␤, or, more abundantly, cleavage in the nonamyloidogenic pathway leads to a soluble APP and a membrane-bound C-terminal fragment. Cleavage in the amyloidogenic pathway is mediated by ␤-and ␥-secretase and in the nonamyloidogenic pathway by ␣-secretase (summarized by Hardy, 1997;Selkoe, 1999). Despite numerous efforts, the molecular identities of the secretases have not yet been fully established.…”

Section: Introductionmentioning

confidence: 99%

Axonal Membrane Proteins Are Transported in Distinct Carriers: A Two-Color Video Microscopy Study in Cultured Hippocampal Neurons

Kaether

Skehel²,

Dotti

2000

MBoC

253

226

View full text Add to dashboard Cite

Neurons transport newly synthesized membrane proteins along axons by microtubule-mediated fast axonal transport. Membrane proteins destined for different axonal subdomains are thought to be transported in different transport carriers. To analyze this differential transport in living neurons, we tagged the amyloid precursor protein (APP) and synaptophysin (p38) with green fluorescent protein (GFP) variants. The resulting fusion proteins, APP-yellow fluorescent protein (YFP), p38-enhanced GFP, and p38-enhanced cyan fluorescent protein, were expressed in hippocampal neurons, and the cells were imaged by video microscopy. APP-YFP was transported in elongated tubules that moved extremely fast (on average 4.5 m/s) and over long distances. In contrast, p38-enhanced GFP-transporting structures were more vesicular and moved four times slower (0.9 m/s) and over shorter distances only. Two-color video microscopy showed that the two proteins were sorted to different carriers that moved with different characteristics along axons of doubly transfected neurons. Antisense treatment using oligonucleotides against the kinesin heavy chain slowed down the long, continuous movement of APP-YFP tubules and increased frequency of directional changes. These results demonstrate for the first time directly the sorting and transport of two axonal membrane proteins into different carriers. Moreover, the extremely fast-moving tubules represent a previously unidentified type of axonal carrier.

show abstract

“…Consequently, Ah has been the focus of intense investigation, and there are now several lines of convincing evidence that Ah is critically involved in the pathogenesis of AD. Patients with familial AD resulting from mutations in the APP, presenilin 1 (PS1), or presenilin 2 (PS2) genes exhibit a marked increase in Ah production and deposition into senile plaques (Hardy, 1997;Hutton and Hardy, 1997). Overproduction of Ah and its deposition into senile plaques are also frequently observed in sporadic AD cases (Ray et al, 1998;Saido, 1998).…”

Section: Introductionmentioning

confidence: 99%