Enlargement of synaptic size as a compensative reaction in aging and dementia

Bertoni–Freddari, Carlo; Fattoretti, Patrizia; Pieroni, Maurizio; Meier‐Ruge, W.; Ulrich, J.

doi:10.1016/s0344-0338(11)80066-x

Cited by 20 publications

(13 citation statements)

References 15 publications

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“…Several studies report that mitochondria in old animals decrease in number but increase in size, maintaining the mitochondrial volume fraction (Bertoni-Freddari et al, 1993, 2006; Solmi et al, 1994). This phenomenon, together with synaptic enlargement during aging (Bertoni-Freddari et al, 1992), may support our finding of no bioenergetic defects in synaptic terminals from aging striatum.…”

Section: Discussionsupporting

confidence: 86%

Intrinsic Bioenergetic Properties and Stress Sensitivity of Dopaminergic Synaptosomes

Choi

Gerencser²,

Lee³

et al. 2011

J. Neurosci.

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Dopaminergic neurons of the substantia nigra pars compacta are defective in Parkinson’s disease, but the specificity of this dysfunction is not understood. One hypothesis is that mitochondrial bioenergetic capacity is intrinsically lower in striatal dopaminergic presynaptic nerve varicosities, making them unusually susceptible to inhibition of electron transport by oxidative damage. To test this hypothesis, we separated isolated synaptosomes bearing dopamine transporters using immunomagnetic beads and compared their respiration with that of the residual nondopaminergic synaptosomes. As predicted, dopaminergic synaptosomes from striatum had lower respiratory rates. However, so did dopaminergic synaptosomes from cortex, indicating a lack of the predicted striatal specificity. We used fluorescent probes to analyze the bioenergetic competence of individual synaptosomes in the two fractions. The respiratory differences became nonsignificant when respiration rates were normalized to the number of respiration-competent synaptosomes, suggesting that differences reflected the quality of the different fractions. To circumvent damage induced by synaptosomal separation, we monitored membrane potentials in whole unseparated single synaptosomes using fluorescent imaging, and then identified the dopaminergic subpopulation using a fluorescent dopamine transporter substrate (ASP+ [4-(4-diethylaminostyryl)-N-methylpyridinium iodide]). The capacity of dopaminergic and nondopaminergic synaptosomes to maintain plasma membrane and mitochondrial membrane potential under several stresses did not differ. In addition, this capacity did not decline in either subpopulation with age, a risk factor for Parkinson’s disease. We conclude that the intrinsic bioenergetic capacities of dopaminergic and nondopaminergic presynaptic synaptosomes from mice do not differ.

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Section: Discussionsupporting

confidence: 86%

Intrinsic Bioenergetic Properties and Stress Sensitivity of Dopaminergic Synaptosomes

Choi

Gerencser²,

Lee³

et al. 2011

J. Neurosci.

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“…therefore, the positive biological sig nificance of this parameter is controversial. We found that both in aging of laboratory ani mals and human beings, the average area of the synaptic contact zones significantly in creases in a comparison with the values found in adult individuals [8,9,25], The synaptic size distribution reported in figure 3 shows that the significant enlargement of the synap tic average area in aging and SDAT is due to an increase of a subpopulation of larger con tacts accounting for different percentages of the whole number of hippocampal and cere bellar contact zones. The increase of synaptic size in aging is questioned by some authors [12,26], however larger contact zones have been found in different CNS areas and even in bioptic and autoptic samples from patients suffering from Alzheimer's disease [10,11].…”

Section: Average Area Of the Synaptic Contact Zonesmentioning

confidence: 53%

“…1. Summary of the results of the authors' morphometric stud ies on human synaptic junctions in physiological aging and SDAT [8,25]. Nv = Synaptic numerical den sity; S = average area of the synap tic contact zones; Sv = synaptic sur face density.…”

Section: Synaptic Surface Densitymentioning

confidence: 99%

Synaptic Structural Dynamics and Aging

et al. 1996

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Synaptic junctional areas are not immutable structures, on the contrary, they are remodelled throughout the individual’s life-span as a consequence of environmental stimulations. This adaptive capacity of the synapses is discussed from a morphological standpoint with reference to aging. In old subjects, the number of contacts and the total surface area of synaptic appositions per unit volume of tissue decrease significantly, while the average synaptic size increases at a different extent according to the CNS area taken into account. This increase in synaptic average area is due to a higher percent of a subpopulation of enlarged contacts supposed to represent either the degenerating junctional zones or a compensatory phenomenon counteracting the synaptic reduction in number. Recent studies on perforated synapses support that the enlarged junctions are possible intermediates in synaptic physiological restructuring, thus the higher percentage of this type of contacts in the old CNS may witness unaccomplished synaptic turnover cycles. Taking into account the high metabolic rate of nerve cells, an age-related impairment in energy provision at synaptic terminal regions may constitute an early and subtle alteration affecting synaptic dynamic morphology in aging.

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“…Interestingly, it has been documented that the average synaptic area in the dentate gyrus and frontal cortex was significantly larger in AD brains than in age-matched controls (39,40). This particular ultrastructural abnormality could be a result of the accumulation of fused synaptic vesicles at the synapse.…”

Section: Discussionmentioning

confidence: 98%

β-Amyloid-induced Dynamin 1 Depletion in Hippocampal Neurons

Kelly

Vassar

Ferreira

2005

Journal of Biological Chemistry

118

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Synaptic dysfunction is one of the earliest events in the pathogenesis of Alzheimer disease (AD). However, the molecular mechanisms underlying synaptic defects in AD are largely unknown. We report here that ␤-amyloid (A␤), the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that is essential for synaptic vesicle recycling and, hence, for memory formation and information processing. The A␤-induced dynamin 1 decrease occurred in the absence of overt synaptic loss and was also observed in the Tg2576 mouse model of AD. In addition, our results provided evidence that the A␤-induced decrease in dynamin 1 was likely the result of a calpain-mediated cleavage of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. These data suggest a mechanism to explain the early cognitive loss without a major decline in synapse number observed in AD and propose a novel therapeutic target for AD intervention.Senile plaques, neurofibrillary tangles, synapse loss, and gross neurodegeneration are common findings in the brain of AD 1 patients (1-4). Numerous genetic, biochemical, and animal model studies have implicated the gradual buildup of A␤, the main component of senile plaques, as the catalyst for AD. However, the mechanistic link between A␤ accumulation and the progressive cognitive impairment associated with this disease has not been elucidated. Synapse loss seems to be the best morphological correlate of the functional deficits observed in the mid-to-late stages of AD (3, 4). In contrast, patients in the earliest stages of the disease show no significant decline in synapse number (5). Based on these findings, it has been hypothesized that a stage of synaptic dysfunction might precede frank synapse loss, plaque accumulation, and tangle formation in AD (6, 7). The mechanisms underlying such synaptic dysfunction remain unknown. It is tempting to speculate that proteins involved in synaptic vesicle biogenesis and/or recycling might play a critical role in AD. Data obtained recently seem to support this view. Thus, changes in the levels of a number of presynaptic proteins, including SNAP-25, syntaxin, and synaptotagmin, have been reported in AD (8). More recently, dynamin 1, a protein highly enriched in presynaptic terminals, has been shown to be significantly reduced in AD brains (9). Dynamin 1, a well studied neuron-specific mechanochemical GTPase, pinches off synaptic vesicles, freeing them from the membrane and allowing them to re-enter the synaptic vesicle pool to be refilled for future release (10, 11). The essential role for dynamin 1 in vesicle scission and synaptic function has been best supported by studies of the Drosophila model shibire, a temperature-sensitive mutant of a dynamin ortholog (12, 13). At restrictive temperatures these flies displayed a paralysis phenotype. This functional deficit was accompanied by the depletion of synaptic vesicles and the accumulation of invaginated pits at pre-synaptic membranes adjacent to the synaptic clefts. Collective...

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Enlargement of synaptic size as a compensative reaction in aging and dementia

Cited by 20 publications

References 15 publications

Intrinsic Bioenergetic Properties and Stress Sensitivity of Dopaminergic Synaptosomes

Intrinsic Bioenergetic Properties and Stress Sensitivity of Dopaminergic Synaptosomes

Synaptic Structural Dynamics and Aging

β-Amyloid-induced Dynamin 1 Depletion in Hippocampal Neurons

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