Alzheimer's disease proteins in cerebellar and hippocampal synapses during postnatal development and aging of the rat

Ribaut‐Barassin, Catherine; Dupont, Jean‐Luc; Haeberlé, Anne-Marie; Bombarde, Guy; Huber, G.; Moussaoui, Saliha; Mariani, Jean; Bailly, Yannick

doi:10.1016/s0306-4522(03)00332-4

Cited by 31 publications

(30 citation statements)

References 94 publications

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“…13 The main hypothesis suggesting the implication of the cerebellum in dementia invokes a possible role for diaschisis, 13,23,30 but our results show that cerebellar volume reductions can be observed even at early stages of the disease. Moreover, there are reports that secondarily affected regions could present mild atrophy and no histopathological changes, 33 and this is what we investigated here. Possible reasons for cerebellar volume reductions in dementia include vascular factors, toxins (e.g.…”

Section: Cerebellar Morphology In Dementiasupporting

confidence: 61%

“…32 Therefore, in these 'secondarily' affected regions, despite the presence of mild atrophy, there is evidence that no relevant histopathological changes are visible under microscopic examination. 33 Diaschisis is the cerebellar reduction related to the atrophy of superior structures and is commonly observed at late stages of dementia. 13 The main hypothesis suggesting the implication of the cerebellum in dementia invokes a possible role for diaschisis, 13,23,30 but our results show that cerebellar volume reductions can be observed even at early stages of the disease.…”

Section: Cerebellar Morphology In Dementiamentioning

confidence: 99%

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Cerebellar volume in patients with dementia

Baldaçara¹,

Borgio²,

Moraes³

et al. 2011

Rev. Bras. Psiquiatr.

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Objective: The aim of this study was to examine the cerebellar volume of subjects at different stages of Alzheimer's disease and to investigate whether volume reductions in this structure are related to cognitive decline. Method: Ninety-six subjects from an epidemiological study were submitted to a magnetic resonance imaging scan and evaluated using the Mini-Mental State Examination and the Functional Activities Questionnaire. Subjects were divided into five groups according to the Clinical Dementia Rating scale. Twenty-six subjects from the original group who had no dementia diagnosis at baseline were re-evaluated for the onset of dementia after two years. Results: The volumes of the cerebellar hemispheres, posterior cerebellar lobe, vermis and temporal lobe were found to be reduced as a function of the severity of the disease. There were significant positive correlations between the volume of the temporal lobe and cerebellum and the language, attention, and total scores in the Mini-Mental State Examination and the Functional Activities Questionnaire. A logistic regression analysis demonstrated that reduced temporal lobe, posterior cerebellar lobe and vermal volume at baseline is a risk factor for the onset of dementia. Conclusion: This is the first study demonstrating that reduced cerebellar volume is already apparent at the predementia stage. The results of this study support the involvement of the cerebellum in the progression of dementia. Whereas the cerebellum might not be directly associated with the origin of Alzheimer's disease, it may provide useful information related to its prognosis. Descriptors

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Section: Cerebellar Morphology In Dementiasupporting

confidence: 61%

Section: Cerebellar Morphology In Dementiamentioning

confidence: 99%

Cerebellar volume in patients with dementia

Baldaçara¹,

Borgio²,

Moraes³

et al. 2011

Rev. Bras. Psiquiatr.

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“…Furthermore, APP, presenilins, and synaptophysin have been shown to co-localize at the growth cones of developing cultured neurons. 38 In summary, it is reasonable to conclude that A␤ deposits play an important role in degeneration of presynaptic structures and therefore have considerable impact on local synaptic connectivity.…”

Section: Alterations In Sipb Morphology Due To A␤ Depositsmentioning

confidence: 95%

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

Rutten

Kolk

Schäfer

et al. 2005

The American Journal of Pathology

107

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Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD).Recently, we observed substantial age-related hippocampal neuron loss in APP751 SL /PS1 M146L transgenic mice but not in PS1 M146L mice. Here, we investigated APP751 SL mice, PS1 M146L mice, and APP751 SL / PS1 M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysinimmunoreactive presynaptic boutons (SIPBs). Wildtype mice, APP751 SL mice and PS1 M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751 SL mice and PS1 M146L mice showed age-related SIPB loss within SR. Importantly, APP751 SL /PS1 M146L mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular A␤ deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. Alzheimer's disease (AD) is a progressive neurodegenerative disorder comprising cognitive and memory deterioration, progressive impairment of activities of daily living, and several neuropsychiatric symptoms. 1 The neuropathology of AD is characterized by disturbances in neural circuits, such as loss of neurons and synapses, and by protein aggregations of ␤-amyloid and hyperphosphorylated tau. 2-4 Accumulating evidence has indicated a crucial role for failure and loss of synapses in AD pathophysiology. 2,4,[5][6][7] Postmortem morphological studies on AD neuropathology have demonstrated significantly reduced synaptic connectivity in brain regions such as the neocortex and hippocampus. 3,6,7 Reductions in synaptic densities showed a strong correlation with cognitive decline in AD. 5 However, the reasons for the reduced connectivity in AD remain poorly understood. 8 According to the "␤-amyloid (A␤) hypothesis of AD," A␤ accumulation is the primary driving force in AD pathogenesis. This hypothesis is supported by the fact that mutations in the amyloid precursor protein (APP) and in presenilin (PS) 1 and PS2, causing early-onset cases of AD, modify APP processing and result in enhanced generation of A␤. 4 We have developed a transgenic mouse model of AD expressing human mutant APP751 (carrying the Swedish and London mutations KM670/671NL and

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“…Also, by analyzing immuno-isolated APP-carrying transport vesicles, only a-but not the other secretases were found to colocalize in these vesicles (Szodorai et al 2009). g-secretase is present in synapses/distal axons (Beher et al 1999;Ribaut-Barassin et al 2003;Inoue et al 2009;Frykman et al 2010); therefore Ab could be produced there, but the precise subcellular site(s) of APP processing by b-and g-secretase in neurons remains to be determined.…”

Section: Subcellular Sites Of G-secretase-mediated App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

913

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Alzheimer's disease proteins in cerebellar and hippocampal synapses during postnatal development and aging of the rat

Cited by 31 publications

References 94 publications

Cerebellar volume in patients with dementia

Cerebellar volume in patients with dementia

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

Trafficking and Proteolytic Processing of APP

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