β-Amyloid Protein Induces Platelet Aggregation and Supports Platelet Adhesion

Kowalska, MA; Badellino, Karen O.

doi:10.1006/bbrc.1994.2883

Cited by 50 publications

(30 citation statements)

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“…When our laboratories and others started this research, the use of drugs enhancing CREB activation was envisioned as a strategy that could work at the downstream level of Aβ and was therefore probably devoid of any putative side effect due the physiological function/s of APP and its downstream products, as well as the secretases responsible for APP processing [19,20,[193][194][195][196][197]. Nevertheless, should drugs acting onto amyloid deposition or even drugs interfering with NFT formation provide a safe and effective approach against AD, one can envision a scenario in which agents enhancing CREB activation are given in a combination therapy with anti-Aβ and/or anti-tau therapies.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

et al. 2015

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Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription).

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Section: Discussionmentioning

confidence: 99%

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

et al. 2015

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“…The actions of A␤ show great selectivity in that only A␤ 1-40 is active, shorter fragments of A␤ and a peptide with the reverse sequence are inactive, while the A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] peptide is only 25% active. Moreover, point mutations alter the activity of A␤, with the G21 mutant showing no activity and the Q22 mutant showing a 90% reduction in platelet-directed activity.…”

Section: Discussionmentioning

confidence: 99%

“…The A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide was inactive. Similarly, A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] showed only weak (25%) enhancement of platelet aggregation, and the reverse sequence, A␤ 40-1 , was also inactive. Co-incubation of A␤ [25][26][27][28][29][30][31][32][33][34][35] with A␤ 1-40 prevented the A␤-mediated augmentation of platelet aggregation (Figure 2a).…”

Section: A␤ Augments Platelet Aggregationmentioning

confidence: 99%

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β-Amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants

Wolozin

Maheshwari²,

Jones³

et al. 1998

Mol Psychiatry

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The ␤-amyloid (A␤) peptide is present both in serum and in platelets, however it is unclear whether A␤ plays a role in platelet function. We have now investigated the effects of soluble A␤ on platelet function and have found that low levels (0.1-1 nM) of soluble A␤ augment ADP-dependent platelet aggregation and translocation of focal adhesion kinase to the platelet cytoskeleton. Addition of A␤ to gel-filtered platelets along with concentrations of adenosine diphosphate (ADP) producing submaximal aggregation responses increased the aggregation response by over 2-fold depending on the ADP:A␤ ratios. The structure activity requirements for A␤ activity showed intriguing constraints. Only full length A␤ has significant activity. Truncated A␤ peptides, such as A␤ 1-16 or A␤ 25-35 , or reverse A␤ 40-1 all show little or no activity. We also examined the activity of mutant A␤ peptides, corresponding with the APP 692A→G and APP 693E→Q (at A␤21 and A␤22, respectively) which are found in familial Alzheimer's disease and hereditary cerebral hemorrhagic amyloidosis, Dutch type (HCHWA-D), and found that these peptides showed little or no activity. These results suggest that A␤ interacts with platelets in a highly specific manner and may play a role in regulating platelet function.

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“…Blocking Aβ production has targeted BACE [123], γ-secretase inhibitors [124], modulating APP synthesis, [125] and the upregulation of α-secretase [126]. However, the role of APP, Aβ , and the secretases in normal physiological function [127][128][129][130] presents a problem in providing effective and safe approaches to AD therapy. As we have described above, APP has neuroprotective properties that may be mediated by cGMP/PKG signaling [50].…”

Section: Relevance To the Amyloid Cascadementioning

confidence: 99%

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

Thatcher

Bennett²,

Reynolds³

2005

CAR

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Nitric oxide is multifunctional messenger molecule in the brain, playing important roles including in learning and memory and in regulating the expression of trophic factors that may be reduced with aging. Small molecules that mimic the biological activity of NO, NO mimetics, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia in Alzheimer's disease. Activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of effective neuroprotective pathways mediated by NO. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia. GT 1061 is an NO mimetic compound currently in clinical trials for Alzheimer's. A survey of current research indicates that NO mimetics will provide a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.

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β-Amyloid Protein Induces Platelet Aggregation and Supports Platelet Adhesion

Cited by 50 publications

References 0 publications

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

Synaptic Therapy in Alzheimer's Disease: A CREB-centric Approach

β-Amyloid augments platelet aggregation: reduced activity of familial angiopathy-associated mutants

Nitric Oxide Mimetic Molecules as Therapeutic Agents in Alzheimers Disease

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