The septo-hippocampal pathway in patients suffering from senile dementia of Alzheimer's type. Evidence for neuronal plasticity?

Gertz, Hermann‐Josef; Cervós-Navarro, J.; Ewald, Victória A Müller

doi:10.1016/0304-3940(87)90720-8

Cited by 49 publications

(22 citation statements)

References 20 publications

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“…Numerous studies have shown that in response to denervation, target sites initiate a plasticity response that is capable of replacing lost synaptic contacts, resulting in a reorganization of some brain circuitry [31,323. Several studies reported evidence of plasticity in AD 15, [33][34][35], suggesting that the entorhinal cortex may also be capable of the same compensatory response. Key brain structures that project to the entorhinal cortex have been shown to have significant neuronal change as a result of AD C36-381, perhaps providing the stimulus for such plasticity.…”

Section: Discussionmentioning

confidence: 96%

Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease

Sparks

Price

1993

Annals of Neurology

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We quantified the synaptic density in the entorhinal cortex (Brodmann area 28) in autopsy material from 10 individuals with Alzheimer's disease and compared them to 11 age-matched, postmortem-matched control subjects without dementia, using standard electron microscopy. The statistical data showed no change in synaptic density between control and Alzheimer subjects, in either lamina III or V of the cortex. There were no correlations between synaptic density and synaptic apposition length or density of senile plaques. The entorhinal cortex stands in marked contrast to other cortical areas that show a significant decline in synaptic numbers with Alzheimer's disease. This preservation of synaptic numbers may be related to a plasticity response that is greater in the entorhinal area than in other areas of the cortex.

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Section: Discussionmentioning

confidence: 96%

Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease

Sparks

Price

1993

Annals of Neurology

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“…The long time interval among synaptic, electrophysiological, and behavioral deficits and plaque accumulation and gliosis was not expected and is important for understanding the course of disease and the development of therapeutic strategies beneficial to early treatment. Therapeutic interventions that protect against early deficits, such as reduced spine density, are important based on those deficits observed in human AD postmortem tissue (23)(24)(25)(26)(27). Additionally, the direct analysis of spine densities is likely to provide a more sensitive measure of synaptic numbers than densitometric analysis of synaptophysin immunoreactivity levels (28).…”

Section: Discussionmentioning

confidence: 99%

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

Jacobsen

Wu²,

Redwine³

et al. 2006

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

639

472

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of ␤-amyloid (A␤)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the A␤42͞A␤40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until Ϸ18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition. ␤-amyloid ͉ cognitionA lzheimer's disease (AD), a progressive neurodegenerative disease of the elderly, is the most common cause of dementia. Characteristic pathologies develop in the brain of AD patients, including senile plaques composed of ␤-amyloid (A␤), neurofibrillary tangles composed of intracellular hyperphosphorylated microtubule-associated protein tau, as well as dystrophic neurites, diminished synaptic densities, and the loss of neuronal function (1). The amyloid hypothesis suggests that accumulation of A␤ fragments 1-40 and 1-42 is primarily responsible for AD pathology, and that it is the imbalance of A␤ production and A␤ clearance that appears to give rise to neurofibrillary tangle formation and the cognitive impairments associated with AD (2, 3).To better understand disease progression, human amyloid precursor protein (APP) transgenic mouse lines expressing various mutations identified from patients with familial AD have been developed to model the effect of A␤ production and deposition on glial and neuronal structure and function and on cognitive performance (4-6). These models have become crucial to understanding the role of A␤ in AD pathology and for testing novel therapeutic strategies. To test the effects of candidate therapeutic treatments, it is necessary to recognize the type, extent, and onset of pathologies in each model. Variability across models largely reflects the backgroun...

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“…Longer spines have synapses that are less mature and more modifiable (23,24). Examination of post mortem brains from AD patients has shown a loss of dendritic spines (25,26). Dendritic spine loss is also seen in the brains of PDAPP, Tg2576, and J20 APP transgenic mice (27, 28) and in hippocampal slices treated with A␤ (29, 30).…”

mentioning

confidence: 92%

Reversal of long-term dendritic spine alterations in Alzheimer disease models

Smith

Pozueta

Gong

et al. 2009

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

220

178

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Synapse loss is strongly correlated with cognitive impairment in Alzheimer's disease (AD). We have previously reported the loss of dendritic spines and the presence of dystrophic neurites in both the hippocampi of transgenic mice overexpressing amyloid precursor protein (APP) and in the human brain affected with AD. In the studies reported here we have asked whether the acute alterations in dendritic spines induced by A␤, as well as the chronic loss of spine density seen in hAPP transgenic mice, are reversible by treatments that restore the cAMP/PKA/CREB signaling pathway or proteasome function to control levels. The results show that both rolipram and TAT-HA-Uch-L1 restore spine density to near control conditions, even in elderly mice. The results suggest that changes in dendritic structure and function that occur after A␤ elevation are reversible even after long periods of time, and that one could envision therapeutic approaches to AD based on this restoration that could work independently of therapies aimed at lowering A␤ levels in the brain.Alzheimer disease ͉ memory deficit ͉ synaptic plasticity A lzheimer's disease (AD) is the most common cause of dementia in elderly individuals. Brain regions involved in learning, memory, and emotional behaviors (namely, the entorhinal cortex, hippocampus, basal forebrain, and amygdala) are reduced in size in AD patients as a result of the degeneration of synapses and, ultimately, the death of neurons (1). The molecular pathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular amyloid (A␤) plaques (2). The A␤ plaques arise from specific processing of the amyloid precursor protein (APP) that is regulated by the presenilins (PS1 and PS2) (3). The development of A␤ plaques has been successfully achieved in transgenic mice overexpressing mutated forms of APP (4) and is greatly accelerated in transgenic models overexpressing mutated forms of both APP and PS1 (5). APP/PS1 mice display impaired LTP, spatial working memory, and contextual learning as early as 3-4 months of age, and they show deficits in basal synaptic transmission (BST) and spatial reference memory after 5-6 months of age (6).Human studies have shown significant synaptic pathology in AD (7, 8) and have identified synapse loss as a major correlate of cognitive impairment in the disease (9). Studies in APP transgenic mice have shown functional deficits and synaptic loss before the onset of A␤ plaque formation (10-12). A␤ deposition also results in local synaptic abnormalities and breakage of neuronal branches (14). In APP transgenic mice, one of the earliest morphological changes is a reduction of hippocampal volume because of a loss of dendritic mass (14). Finally, A␤ itself is capable of impairing synaptic plasticity independent of plaque formation both in slices and in vivo (15)(16)(17)(18) Dendritic spines are cellular compartments containing the molecular machinery important for synaptic transmission and plasticity (19). In healthy mice, the number of spines on a particular dendr...

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The septo-hippocampal pathway in patients suffering from senile dementia of Alzheimer's type. Evidence for neuronal plasticity?

Cited by 49 publications

References 20 publications

Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease

Quantitative assessment of synaptic density in the entorhinal cortex in Alzheimer's disease

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease

Reversal of long-term dendritic spine alterations in Alzheimer disease models

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