ReviewAltered synaptic function in Alzheimer's disease
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
References (146)
- et al.
N-[3H]methylcarbamylcholine binding sites in the rat and human brain: relationship to functional nicotinic autoreceptors and alterations in Alzheimer's disease
Prog. Brain Res.
(1989) - et al.
Structural involvement of the glutamatergic presynaptic boutons in a transgenic mouse model expressing early onset amyloid pathology
Neurosci. Lett.
(2003) - et al.
NGF-mediated synaptic sprouting in the cerebral cortex of lesioned primate brain
Brain Res.
(1995) - et al.
Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor
J. Biol. Chem.
(1998) - et al.
p75 and Trk: a two-receptor system
Trends Neurosci.
(1995) - et al.
Atrophy of cholinergic basal forebrain neurons following excitotoxic cortical lesions is reversed by intravenous administration of an NGF conjugate
Brain Res.
(1996) - et al.
Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695
J. Biol. Chem.
(2001) - et al.
Selective loss of central cholinergic neurons in Alzheimer's disease
Lancet
(1976) - et al.
The acute neurotoxicity and effects upon cholinergic axons of intracerebrally injected beta-amyloid in the rat brain
Neurobiol. Aging
(1992) - et al.
Nucleus basalis neuronal loss, neuritic plaques and choline acetyltransferase activity in advanced Alzheimer's disease
Neuroscience
(1986)
Animal and drug modelling for Alzheimer synaptic pathology
Prog. Neurobiol.
Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice
Am. J. Pathol.
Senile plaques as aberrant sprout-stimulating structures
Exp. Neurol.
Phosphoinositide hydrolysis, G alpha q, phospholipase C, and protein kinase C in post mortem human brain: effects of post mortem interval, subject age, and Alzheimer's disease
Neuroscience
Responses of basal forebrain cholinergic neurons to damage in the adult brain
Prog. Neurobiol.
Differential modulation of the cholinergic phenotype of the nucleus basalis magnocellularis neurons by applying NGF at the cell body or cortical terminal fields
Exp. Neurol.
The impact of Abeta-plaques on cortical cholinergic and non-cholinergic presynaptic boutons in Alzheimer's disease-like transgenic mice
Neuroscience
Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway
Exp. Neurol.
Impaired phosphoinositide hydrolysis in Alzheimer's disease brain
Neurobiol. Aging
Cholinergic activation of phosphoinositide signaling is impaired in Alzheimer's disease brain
Neurobiol. Aging
APP processing and synaptic function
Neuron
Signal transduction by the neurotrophin receptors
Curr. Opin. Cell Biol.
Ante mortem cerebral amino acid concentrations indicate selective degeneration of glutamate-enriched neurons in Alzheimer's disease
Neuroscience
Patterns of aberrant sprouting in Alzheimer's disease
Neuron
Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein
Neuron
Synaptotrophic effects of human amyloid beta protein precursors in the cortex of transgenic mice
Brain Res.
Reduction in p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimer's disease
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.
Cited by (95)
Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease
2023, European Journal of PharmacologyEffects of vanillic acid on Aβ<inf>1-40</inf>-induced oxidative stress and learning and memory deficit in male rats
2021, Brain Research BulletinRose bengal conjugated gadolinium complex as a new multimodal imaging agent targeting presynaptic vesicular glutamate transporters
2021, Journal of Industrial and Engineering ChemistryEmerging Role of microRNAs in Dementia
2019, Journal of Molecular Biology