Altered synaptic function in Alzheimer's disease

doi:10.1016/j.ejphar.2006.06.045

European Journal of Pharmacology

Volume 545, Issue 1, 1 September 2006, Pages 11-21

https://doi.org/10.1016/j.ejphar.2006.06.045 Get rights and content

Abstract

Alzheimer's disease is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning. Since synaptic density correlates more closely with cognitive impairment than any other pathological lesion observable in the disease pathology, an increased understanding of the mechanisms behind synaptic disconnection is of vital importance. Our lab investigated the neurotransmitter-specific status of distinct cortical presynaptic bouton populations in various transgenic mouse models of the Alzheimer's-like amyloid pathology in order to assess their involvement throughout the progression of the pathology. These studies have revealed that the amyloid pathology appears to progress in a neurotransmitter-specific manner where the cholinergic terminals appear most vulnerable, followed by the glutamatergic terminals and finally by the somewhat more resilient GABAergic terminals. This review will discuss additional studies which also provide evidence of a neurotransmitter-specific pathology as well as comment on the potential explanations for the observed vulnerabilities, touching upon metabolic demand, trophic support and receptor mediated activation.

Section snippets

Importance of synaptic function in the study of Alzheimer's disease

Alzheimer's disease, the current leading cause of dementia in the elderly, is characterized by three hallmark pathological lesions; amyloid plaques, neurofibrillary tangles and synaptic loss. These alterations appear to be at the root of the clinical manifestations of the disease, namely progressive cognitive decline, memory loss and dementia [for review see (Morris et al., 1984, Khachaturian, 1985)]. Perhaps the most extensively investigated lesion within the Alzheimer's disease pathology is

Dystrophic neurite function as it relates to Alzheimer's disease

An additional lesion associated with the Alzheimer pathology, whose importance may have initially been underestimated, is the presence of dystrophic neurites, which can be defined as an abnormal growth of axonal or dendritic terminals (Geddes et al., 1985, Geddes et al., 1986, Masliah et al., 1991). These lesions are generally localized to the plaque periphery, which has lead to the assumption that they arise as a direct result of fibrillar amyloid. Supporting this theory is the study by

The amyloid pathology progresses in a neurotransmitter-specific manner

The preferential recruitment of cholinergic presynaptic boutons (upregulation of cholinergic terminals prior to plaque formation) prior to the involvement of both the glutamatergic and GABAergic terminals, as well as the preferential localization of cholinergic dystrophic neurites to the immediate plaque periphery despite the near absence of GABAergic dystrophic neurites, suggests that a neurotransmitter-specific vulnerability exists in response to the amyloid pathology. We propose that the

Therapeutic relevance and conclusions

The amyloid pathology alone (in the absence of neurofibrillary tangle pathology) appears capable of inducing profound cortical synaptic remodelling in a neurotransmitter-specific manner. Assuming that the Alzheimer's pathology also progresses in a neurotransmitter-specific manner, the added burden of the tau pathology would only serve to further disrupt synaptic connectivity and exacerbate pre-existing vulnerabilities. Thus elucidating the mechanisms between amyloid beta protein deposition and

Acknowledgements

This research was supported by funds from the Canadian Institutes of Health Research to A. Claudio Cuello (grant # MOP-37996). The authors would like to thank Professors Karen Duff, Karen Hsiao, Peter St. George-Hyslop and Don Westaway for their generous donation of transgenic mouse lines and Dr.'s Shigemoto and Edwards for their kind donation of the anti-VGluT1 and anti-VAChT antibodies respectively. The authors would also like to express their sincere gratitude to all of the participants of

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ReviewAltered synaptic function in Alzheimer's disease

Abstract

Section snippets

Importance of synaptic function in the study of Alzheimer's disease

Dystrophic neurite function as it relates to Alzheimer's disease

The amyloid pathology progresses in a neurotransmitter-specific manner

Therapeutic relevance and conclusions

Acknowledgements

Prog. Brain Res.

Neurosci. Lett.

Brain Res.

J. Biol. Chem.

Trends Neurosci.

Brain Res.

J. Biol. Chem.

Lancet

Neurobiol. Aging

Neuroscience

Prog. Neurobiol.

Am. J. Pathol.

Exp. Neurol.

Neuroscience

Prog. Neurobiol.

Exp. Neurol.

Neuroscience

Exp. Neurol.

Neurobiol. Aging

Neurobiol. Aging

Neuron

Curr. Opin. Cell Biol.

Neuroscience

Neuron

Neuron

Brain Res.

Exp. Neurol.

Differential alteration of various cholinergic markers in cortical and subcortical regions of human brain in Alzheimer's disease

J. Neurochem.

Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases

J. Neurochem.

Amyloid Plaque Dependent Glutamatergic Neuritic Dystrophy in the Alzheimer's Disease Brain

The amyloid pathology progresses in a neurotransmitter-specific manner

Neurobiol. Aging

Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis

J. Neurosci.

Functional interactions of neurotrophins and neurotrophin receptors

Annu. Rev. Neurosci.

Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies

Brain

Long-lasting rescue of age-associated deficits in cognition and the CNS cholinergic phenotype by a partial agonist peptidomimetic ligand of TrkA

J. Neurosci.

Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone

Development

Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice

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

Aging causes a preferential loss of cholinergic innervation of characterized neocortical pyramidal neurons

Cereb. Cortex

The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease

J. Neuropathol. Exp. Neurol.

Aminergic systems in Alzheimer's disease and Parkinson's disease

Ann. Neurol.

Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice

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

A nerve growth factor mimetic TrkA antagonist causes withdrawal of cortical cholinergic boutons in the adult rat

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

Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity

Ann.Neurol.

Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment

Ann. Neurol.

Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD

Neurology

Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1

Nature

Cleavage of amyloid beta peptide during constitutive processing of its precursor

Science

The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor

J. Neurochem.

Diminished muscarinic receptor-stimulated [3H]-PIP2 hydrolysis in Alzheimer's disease

Life Sci.

Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease

Mol Chem. Neuropathol.

Review
Altered synaptic function in Alzheimer's disease