Review
Alzheimer's disease and post-operative cognitive dysfunction

https://doi.org/10.1016/j.exger.2006.01.014Get rights and content

Abstract

Alzheimer's disease (AD), an insidious and progressive neurodegenerative disorder accounting for the vast majority of dementia, is characterized by global cognitive decline and the robust accumulation of amyloid deposits and neurofibrillary tangles in the brain. This review article is based on the currently published literature regarding molecular studies of AD and the potential involvement of AD neuropathogenesis in post-operative cognitive dysfunction (POCD). Genetic evidence, confirmed by neuropathological and biochemical studies, indicates that excessive β-amyloid protein (Aβ) generated from amyloidogenic processing of the β-amyloid precursor protein (APP) plays a fundamental role in the AD neuropathogenesis. Aβ is produced from APP by β-secretase, and then γ-secretase complex, consisting of presenilins, nicastrin (NCSTN), APH-1 and PEN-2. Additionally, Aβ clearance and APP adaptor proteins can contribute to AD neuropathogenesis via affecting Aβ levels. Finally, cellular apoptosis may also be involved in AD neuropathogenesis. Surgery and anesthesia can cause cognitive disorders, especially in elderly patients. Even the molecular mechanisms underlying these disorders are largely unknown; several perioperative factors such as hypoxia, hypocapnia and anesthetics may be associated with AD and render POCD via trigging AD neuropathogenesis. More studies to assess the potential relationship between anesthesia/surgery and AD dementia are, therefore, urgently needed.

Introduction

Alzheimer's disease (AD) is one of the greatest public health problems in the US, and its impact will only increase with demographic changes anticipated in the coming decades. At current time, AD affects 4.5 million Americans and cost $100 billion a year on direct care alone. It is estimated that the number of AD patients will reach 13.2 millions in the United States of America by 2050, if no treatments for AD are found.

AD was first described in 1907 by professor Alois Alzheimer, a Bavarian psychiatrist with expertise in neuropathology (Alzheimer, 1907). Clinically, AD patients usually presents with subtle onset of memory loss followed by a slowly progressive dementia with a course of several years. Pathologically, AD patients have gross, diffuse atrophy of the cerebral cortex with secondary enlargement of the ventricular system, and there are neuritic plaques containing β-amyloid protein (Aβ), silver-staining neufibrillary tangles in neuronal cytoplasm, and accumulation of Aβ in arterial walls of cerebral blood vessels. Genetically, identification of several AD genes has provided a foundation for rapid progress in understanding the neuropathogenesis of AD. Numerous environmental factors, including aluminum, mercury, viruses, and prions, have been proposed as causes of AD. Recently, some perioperative factors like hypoxia, hypocapnia and anesthetics have been suggested to contribute to AD neuropathogenesis, and to cause post-operative cognitive dysfunction (POCD) through activating AD neuropathogenesis.

Section snippets

Genetic etiology and their roles in AD neuropathogenesis

While the etiological underpinnings of AD are only partially understood, the inheritance of predisposing genetic factors appears to play a major role. After age, family history is the second greatest risk factor of AD. There is an emerging consensus that AD is complex and genetically heterogeneous disorder that is best explained by an age-dependent dichotomous model (Tanzi, 1999). Early-onset familial AD (EOFAD) mutations are rare, highly penetrant, and transmitted in an autosomal-dominant

Perioperative factors conceivably trigging AD neuropathogenesis

Earlier studies revealed that neurodegenerative disorders, such as AD and Parkinson's disease, might be accelerated by anesthesia and surgery (Bohnen et al., 1994a, Bohnen et al., 1994b, Muravchick and Smith, 1995). There have been numerous reports of delayed and long-lasting post-operative cognitive dysfunction following both cardiac and non-cardiac surgery [(Moller et al., 1998, Newman et al., 2001), reviewed in (Dodds and Allison, 1998)]. The recent international study of post-operative

Conclusion

AD, one of the most serious health problems in the US, is a progressive and insidious neurodegenerative disorder of the central nervous system characterized by global deficits in cognition ranging from loss of memory to impaired judgment and reasoning. Early studies revealed mutations in three genes (APP, PSEN1 and PSEN2) are responsible for up to 50% of early onset cases of FAD, whereas the APOE-ε4 gene variant is a risk factor of later onset AD. Recently, new genes such as α2M, IDE and UBQLIN1

Acknowledgements

This work was supported by the U.S. Public Health Service, AG 014713-07 (NIA), MH 60009-03 (NIMH), K12 (AG 00294-17), K08 (NS048140-01) and P60 (AG008812-15). We thank the Department of Anesthesia and Critical Care at Massachusetts General Hospital and Harvard Medical School for the support and help.

References (213)

  • M.M. Esiri et al.

    Cerebrovascular disease and threshold for dementia in the early stages of Alzheimer's disease

    Lancet

    (1999)
  • W. Farris et al.

    Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein

    Am. J. Pathol.

    (2004)
  • F. Fiore et al.

    The regions of the Fe65 protein homologous to the phosphotyrosine interaction/phosphotyrosine binding domain of Shc bind the intracellular domain of the Alzheimer's amyloid precursor protein

    J. Biol. Chem.

    (1995)
  • R. Francis et al.

    Aph-1 and Pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation

    Dev. Cell

    (2002)
  • N.P. Franks et al.

    Which molecular targets are most relevant to general anaesthesia?

    Toxicol. Lett.

    (1998)
  • F.G. Gervais et al.

    Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic a beta peptide formation

    Cell

    (1999)
  • G.G. Glenner et al.

    Alzheimer's disease and down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein

    Biochem. Biophys. Res. Commun.

    (1984)
  • G.G. Glenner et al.

    Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein

    Biochem. Biophys. Res. Commun.

    (1984)
  • Y. Gu et al.

    Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-like cleavage of Notch

    J. Biol. Chem.

    (2001)
  • Y. Gu et al.

    APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin nicastrin complexes

    J. Biol. Chem.

    (2003)
  • J. Hardy

    Amyloid, the presenilins and Alzheimer's disease

    Trends Neurosci.

    (1997)
  • T. Hiesberger et al.

    Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation

    Neuron

    (1999)
  • C.S. Ho et al.

    Synergistic effects of Munc18a and X11 proteins on amyloid precursor protein metabolism

    J. Biol. Chem.

    (2002)
  • I. Hussain et al.

    Identification of a novel aspartic protease (Asp 2) as beta-secretase

    Mol. Cell Neurosci.

    (1999)
  • H. Inomata et al.

    A scaffold protein JIP-1b enhances amyloid precursor protein phosphorylation by JNK and its association with kinesin light chain 1

    J. Biol. Chem.

    (2003)
  • K.A. Jellinger

    The pathology of ischemic-vascular dementia: an update

    J. Neurol. Sci.

    (2002)
  • R.N. Kalaria

    The role of cerebral ischemia in Alzheimer's disease

    Neurobiol. Aging

    (2000)
  • D.Y. Kim et al.

    Nectin-1alpha, an immunoglobulin-like receptor involved in the formation of synapses, is a substrate for presenilin/gamma-secretase-like cleavage

    J. Biol. Chem.

    (2002)
  • S.H. Kim et al.

    Regulated hyperaccumulation of presenilin-1 and the gamma-secretase complex. Evidence for differential intramembranous processing of transmembrane substrates

    J. Biol. Chem.

    (2003)
  • S. Kvolik et al.

    Effects of inhalation anesthetics halothane, sevoflurane, and isoflurane on human cell lines

    Life Sci.

    (2005)
  • S. Lammich et al.

    Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide

    J. Biol. Chem.

    (2002)
  • J. Larson et al.

    Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice

    Brain Res.

    (1999)
  • M.J. LaVoie et al.

    Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin

    J. Biol. Chem.

    (2003)
  • S.F. Lee et al.

    Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch

    J. Biol. Chem.

    (2002)
  • M.A. Leissring et al.

    Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death

    Neuron

    (2003)
  • X. Li et al.

    Membrane topology of the C. elegans SEL-12 presenilin

    Neuron

    (1996)
  • H. Loetscher et al.

    Presenilins are processed by caspase-type proteases

    J. Biol. Chem.

    (1997)
  • A. Alzheimer

    Uber eine eigenartige Erkrankung der Hirnrinde

    Allg. Zeitschr. Psychiatr. Psychiatr-Gerichtl. Med.

    (1907)
  • P.V. Arriagada et al.

    Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease

    Neurology

    (1992)
  • N.Y. Barnes et al.

    Increased production of amyloid precursor protein provides a substrate for caspase-3 in dying motoneurons

    J. Neurosci.

    (1998)
  • D.A. Bennett et al.

    Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function

    Arch. Neurol.

    (2004)
  • L. Bertram et al.

    Evidence for genetic linkage of Alzheimer's disease to chromosome 10q

    Science

    (2000)
  • L. Bertram et al.

    Family-based association between Alzheimer's disease and variants in UBQLN1

    N. Engl. J. Med.

    (2005)
  • T. Biederer et al.

    Regulation of APP-dependent transcription complexes by mint/X11s: differential functions of mint isoforms

    J. Neurosci.

    (2002)
  • D. Blacker et al.

    Results of a high-resolution genome screen of 437 Alzheimer's disease families

    Hum. Mol. Genet.

    (2003)
  • N. Bohnen et al.

    Early and midlife exposure to anesthesia and age of onset of Alzheimer's disease

    Int. J. Neurosci.

    (1994)
  • N.I. Bohnen et al.

    Alzheimer's disease and cumulative exposure to anesthesia: a case–control study

    J. Am. Geriatr. Soc.

    (1994)
  • J.P. Borg et al.

    The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein

    Mol. Cell Biol.

    (1996)
  • J.A. Campagna et al.

    Mechanisms of actions of inhaled anesthetics

    N. Engl. J. Med.

    (2003)
  • X. Cao et al.

    A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase tip60

    Science

    (2001)
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