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

Abstract

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

Modification upon aging of the density of presynaptic modulation systems in the hippocampus

“…Therefore, it is concluded that there is a modification of the density of the tested proteins associated with the vesicular release apparatus which might slightly increase during adulthood and then significantly decreases upon aging. This age-related decrease of presynaptic markers is in general agreement with the majority of studies reporting a decrease in synaptophysin mRNA and protein density and in the number of elements immuno-positive for synaptophysin with aging in the hippocampus and various cortical structures (Chen et al, 1995;Eastwood et al, 1994;Frick and Fernandez, 2003;King and Arendash, 2002;Masliah et al, 1993;Rutten et al, 2005;Saito et al, 1994), albeit some studies reported lack of modification (Calhoun et al, 1998;Eastwood et al, 2006;Nicolle et al, 1999a) and even increases (Benice et al, 2006;Himeda et al, 2005) in the density of this presynaptic marker.…”

Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: Relationship with the progression of Alzheimer's disease

“…This observation was confirmed in 11 cases with stereologic assessment of total amyloid volumes. Also, consistent with recent animal and human studies, our results point to the necessity to explore the effect of Aβ oligomers in AD-related loss of postsynaptic elements (for review see [12,36,37,55]. The relationship between synaptic loss and NFT burden is still a matter of debate.…”

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

“…The semiquantitative results indicated that the density of SIPBs was markedly decreased in the CA3 subfield of the hippocampus in the vehicle-treated APP/PS1 mice compared with the vehicle-treated wild-type controls (Fig. 5 A, B), consistent with a previous report (Rutten et al, 2005). The decreased density of SIPBs was completely reversed in the ATRA-treated APP/PS1 mice compared with the vehicle-treated APP/PS1 mice (Fig.…”

“…Neuronal degeneration and loss observed in the brains of AD patients (West et al, 1994) and in the brains of APP/PS1 transgenic mice (Fonseca et al, 2004;Rutten et al, 2005) is hypothesized to be exacerbated by an inflammatory reaction (McGeer and McGeer, 1999). Given the inhibitory effect of ATRA on glial activation, an indicator of CNS inflammation, we determined the effect of ATRA on neuronal integrity.…”