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Angiotensins and Alzheimer's disease: a bench to bedside overview.

Kehoe PG - Alzheimers Res Ther (2009)

Bottom Line: The pathology of Alzheimer's disease (AD) features amyloid beta peptide deposition, intracellular neurofibrillary tangles and deficits in the cholinergic pathway.Abnormal blood pressure is recognised as a risk factor for the development of AD, although the underlying mechanisms remain unproven.This review proposes angiotensins and associated enzymatic pathways as important mediators of recognised but undefined links between blood pressure and AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dementia Research Group, Institute of Clinical Neurosciences, Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, UK. Patrick.Kehoe@bristol.ac.uk.

ABSTRACT
The pathology of Alzheimer's disease (AD) features amyloid beta peptide deposition, intracellular neurofibrillary tangles and deficits in the cholinergic pathway. Abnormal blood pressure is recognised as a risk factor for the development of AD, although the underlying mechanisms remain unproven. This review proposes angiotensins and associated enzymatic pathways as important mediators of recognised but undefined links between blood pressure and AD. Evidence in support of this involvement translates consistently from the most basic in vitro, in vivo and ex vivo experimental paradigms to more complex human-based observational and experimental studies, which also fortunately offer potential for therapeutic interventions against AD.

No MeSH data available.


Related in: MedlinePlus

Schematic of amyloid precurser protein metabolism, from which amyloid β peptide can be produced. The amyloid precurser protein (APP) amino acid sequence is given in the single letter code with the boxed sequence representing the amyloid β peptide (Aβ). The red arrows denoted by β and γ represent the major β- and γ-secretase cleavage sites on APP from which Aβ is produced in the amyloidogenic pathway. The green arrow denoted by α pointing to the highlighted lettering shows the vicinity of the major α-secretase site on APP, which precludes the formation of APP in the anti-amyloidogenic pathway. The blue arrows labelled ACE show the proposed amino acids that are involved in (anti-amyloidogenic denoted by a question mark) ACE-mediated cleavage of Aβ, which were suggested to be either Asp7-Ser8 based on the detection of Aβ8–40 fragments or Arg5-His6 [8,32]. Interestingly, isomerisation (that is, having the same molecular formula but having a different structure and sometimes different properties) of the Asp7 (isoAsp7) residue of Aβ, a common age-related and possible conformational modification that is more prevalent in Alzheimer's disease (AD), resulted in more efficient cleavage than the non-modified Asp7             in vitro. It has thus been suggested that the main cleavage site of angiotensin-1 converting enzyme could be Arg5-His6 and the identification of Aβ8–40 cleavage products detected previously might be the result of subsequent hydrolysis of Aβ6–40 fragments. The blue horizontal arrows of different sizes and pointing in opposite directions indicate that the majority of APP processing throughout a lifetime is anti-amyloidogenic but that in AD there is evidence of some increased amyloidogenic processing (denoted by the dashed arrow). Negative effects on the cholinergic pathway resulting from Aβ activity are shown, as are reported complex feedbacks between cholinergic receptors and APP processing (see [5] for a review). ChAT, choline acetyltransferase.
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Figure 1: Schematic of amyloid precurser protein metabolism, from which amyloid β peptide can be produced. The amyloid precurser protein (APP) amino acid sequence is given in the single letter code with the boxed sequence representing the amyloid β peptide (Aβ). The red arrows denoted by β and γ represent the major β- and γ-secretase cleavage sites on APP from which Aβ is produced in the amyloidogenic pathway. The green arrow denoted by α pointing to the highlighted lettering shows the vicinity of the major α-secretase site on APP, which precludes the formation of APP in the anti-amyloidogenic pathway. The blue arrows labelled ACE show the proposed amino acids that are involved in (anti-amyloidogenic denoted by a question mark) ACE-mediated cleavage of Aβ, which were suggested to be either Asp7-Ser8 based on the detection of Aβ8–40 fragments or Arg5-His6 [8,32]. Interestingly, isomerisation (that is, having the same molecular formula but having a different structure and sometimes different properties) of the Asp7 (isoAsp7) residue of Aβ, a common age-related and possible conformational modification that is more prevalent in Alzheimer's disease (AD), resulted in more efficient cleavage than the non-modified Asp7 in vitro. It has thus been suggested that the main cleavage site of angiotensin-1 converting enzyme could be Arg5-His6 and the identification of Aβ8–40 cleavage products detected previously might be the result of subsequent hydrolysis of Aβ6–40 fragments. The blue horizontal arrows of different sizes and pointing in opposite directions indicate that the majority of APP processing throughout a lifetime is anti-amyloidogenic but that in AD there is evidence of some increased amyloidogenic processing (denoted by the dashed arrow). Negative effects on the cholinergic pathway resulting from Aβ activity are shown, as are reported complex feedbacks between cholinergic receptors and APP processing (see [5] for a review). ChAT, choline acetyltransferase.

Mentions: Alzheimer's disease (AD) [MIM 104300], as the most common form of progressive dementia, is characterised neuropathologically by the presence of intracellular neurofibrillary tangles and features resulting from the deposition of amyloid β-peptide (Aβ) extracellularly in the form of senile plaques and within blood vessels in the brain in the form of cerebral amyloid angiopathy. The pathogenesis of AD is understood to be partly explained by mechanisms involved with (but not restricted to) two of the most prevailing hypotheses: the Aβ cascade hypothesis and the cholinergic hypothesis. The Aβ cascade hypothesis, which developed in the early 1980s, suggests that the commonly observed neurodegenerative abnormalities of AD, particularly senile plaques, develop following the accumulation of the 39 to 42 amino acid peptide Aβ in the brain [1]. This accumulation of Aβ is likely a consequence of imbalance between production of Aβ from amyloid precursor protein (APP; Figure 1) and its removal. Aβ removal can be mediated via drainage through interstitial fluid in the space surrounding blood vessels in the brain, by receptor-mediated transport of Aβ from the brain to the peripheral circulation, by enzymatic degradation or various combinations of all the these [1]. Over the years the Aβ hypothesis has not been universally accepted due to its perceived failing that brain Aβ deposition correlated poorly with cell death or disease severity in AD whereas neurofibrillary tangle pathology, another established neuropathological hallmark for AD, correlated better and, as such, was suggested to be more relevant, with Aβ representative of a secondary phenomenon [2]. Yet this failing was arguably addressed in the past decade with the identification of soluble and diffusible oligomeric forms of Aβ that are now thought to be the more harmful forms and which have been correlated with AD pathogenesis [3]. Furthermore, questions have now arisen as to whether neurofibrillary tangles are merely a marker of disease progression and not, in fact, a mediator of cell death as has been proposed (see [3,4] for reviews).


Angiotensins and Alzheimer's disease: a bench to bedside overview.

Kehoe PG - Alzheimers Res Ther (2009)

Schematic of amyloid precurser protein metabolism, from which amyloid β peptide can be produced. The amyloid precurser protein (APP) amino acid sequence is given in the single letter code with the boxed sequence representing the amyloid β peptide (Aβ). The red arrows denoted by β and γ represent the major β- and γ-secretase cleavage sites on APP from which Aβ is produced in the amyloidogenic pathway. The green arrow denoted by α pointing to the highlighted lettering shows the vicinity of the major α-secretase site on APP, which precludes the formation of APP in the anti-amyloidogenic pathway. The blue arrows labelled ACE show the proposed amino acids that are involved in (anti-amyloidogenic denoted by a question mark) ACE-mediated cleavage of Aβ, which were suggested to be either Asp7-Ser8 based on the detection of Aβ8–40 fragments or Arg5-His6 [8,32]. Interestingly, isomerisation (that is, having the same molecular formula but having a different structure and sometimes different properties) of the Asp7 (isoAsp7) residue of Aβ, a common age-related and possible conformational modification that is more prevalent in Alzheimer's disease (AD), resulted in more efficient cleavage than the non-modified Asp7             in vitro. It has thus been suggested that the main cleavage site of angiotensin-1 converting enzyme could be Arg5-His6 and the identification of Aβ8–40 cleavage products detected previously might be the result of subsequent hydrolysis of Aβ6–40 fragments. The blue horizontal arrows of different sizes and pointing in opposite directions indicate that the majority of APP processing throughout a lifetime is anti-amyloidogenic but that in AD there is evidence of some increased amyloidogenic processing (denoted by the dashed arrow). Negative effects on the cholinergic pathway resulting from Aβ activity are shown, as are reported complex feedbacks between cholinergic receptors and APP processing (see [5] for a review). ChAT, choline acetyltransferase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719108&req=5

Figure 1: Schematic of amyloid precurser protein metabolism, from which amyloid β peptide can be produced. The amyloid precurser protein (APP) amino acid sequence is given in the single letter code with the boxed sequence representing the amyloid β peptide (Aβ). The red arrows denoted by β and γ represent the major β- and γ-secretase cleavage sites on APP from which Aβ is produced in the amyloidogenic pathway. The green arrow denoted by α pointing to the highlighted lettering shows the vicinity of the major α-secretase site on APP, which precludes the formation of APP in the anti-amyloidogenic pathway. The blue arrows labelled ACE show the proposed amino acids that are involved in (anti-amyloidogenic denoted by a question mark) ACE-mediated cleavage of Aβ, which were suggested to be either Asp7-Ser8 based on the detection of Aβ8–40 fragments or Arg5-His6 [8,32]. Interestingly, isomerisation (that is, having the same molecular formula but having a different structure and sometimes different properties) of the Asp7 (isoAsp7) residue of Aβ, a common age-related and possible conformational modification that is more prevalent in Alzheimer's disease (AD), resulted in more efficient cleavage than the non-modified Asp7 in vitro. It has thus been suggested that the main cleavage site of angiotensin-1 converting enzyme could be Arg5-His6 and the identification of Aβ8–40 cleavage products detected previously might be the result of subsequent hydrolysis of Aβ6–40 fragments. The blue horizontal arrows of different sizes and pointing in opposite directions indicate that the majority of APP processing throughout a lifetime is anti-amyloidogenic but that in AD there is evidence of some increased amyloidogenic processing (denoted by the dashed arrow). Negative effects on the cholinergic pathway resulting from Aβ activity are shown, as are reported complex feedbacks between cholinergic receptors and APP processing (see [5] for a review). ChAT, choline acetyltransferase.
Mentions: Alzheimer's disease (AD) [MIM 104300], as the most common form of progressive dementia, is characterised neuropathologically by the presence of intracellular neurofibrillary tangles and features resulting from the deposition of amyloid β-peptide (Aβ) extracellularly in the form of senile plaques and within blood vessels in the brain in the form of cerebral amyloid angiopathy. The pathogenesis of AD is understood to be partly explained by mechanisms involved with (but not restricted to) two of the most prevailing hypotheses: the Aβ cascade hypothesis and the cholinergic hypothesis. The Aβ cascade hypothesis, which developed in the early 1980s, suggests that the commonly observed neurodegenerative abnormalities of AD, particularly senile plaques, develop following the accumulation of the 39 to 42 amino acid peptide Aβ in the brain [1]. This accumulation of Aβ is likely a consequence of imbalance between production of Aβ from amyloid precursor protein (APP; Figure 1) and its removal. Aβ removal can be mediated via drainage through interstitial fluid in the space surrounding blood vessels in the brain, by receptor-mediated transport of Aβ from the brain to the peripheral circulation, by enzymatic degradation or various combinations of all the these [1]. Over the years the Aβ hypothesis has not been universally accepted due to its perceived failing that brain Aβ deposition correlated poorly with cell death or disease severity in AD whereas neurofibrillary tangle pathology, another established neuropathological hallmark for AD, correlated better and, as such, was suggested to be more relevant, with Aβ representative of a secondary phenomenon [2]. Yet this failing was arguably addressed in the past decade with the identification of soluble and diffusible oligomeric forms of Aβ that are now thought to be the more harmful forms and which have been correlated with AD pathogenesis [3]. Furthermore, questions have now arisen as to whether neurofibrillary tangles are merely a marker of disease progression and not, in fact, a mediator of cell death as has been proposed (see [3,4] for reviews).

Bottom Line: The pathology of Alzheimer's disease (AD) features amyloid beta peptide deposition, intracellular neurofibrillary tangles and deficits in the cholinergic pathway.Abnormal blood pressure is recognised as a risk factor for the development of AD, although the underlying mechanisms remain unproven.This review proposes angiotensins and associated enzymatic pathways as important mediators of recognised but undefined links between blood pressure and AD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dementia Research Group, Institute of Clinical Neurosciences, Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, UK. Patrick.Kehoe@bristol.ac.uk.

ABSTRACT
The pathology of Alzheimer's disease (AD) features amyloid beta peptide deposition, intracellular neurofibrillary tangles and deficits in the cholinergic pathway. Abnormal blood pressure is recognised as a risk factor for the development of AD, although the underlying mechanisms remain unproven. This review proposes angiotensins and associated enzymatic pathways as important mediators of recognised but undefined links between blood pressure and AD. Evidence in support of this involvement translates consistently from the most basic in vitro, in vivo and ex vivo experimental paradigms to more complex human-based observational and experimental studies, which also fortunately offer potential for therapeutic interventions against AD.

No MeSH data available.


Related in: MedlinePlus