Early Selective Vulnerability of Synapses and Synaptic Mitochondria in the Hippocampal CA1 Region of the Tg2576 Mouse Model of Alzheimer's Disease

Abstract

Increasing experimental evidence indicates that synaptic alterations play a key role in cognitive decline in Alzheimer's disease (AD). Functional and structural synaptic changes progressively take place, beginning in the early phase of AD, mainly triggered by intracellular accumulation of soluble amyloid-β (Aβ) oligomers. These peptides also accumulate within mitochondria, heavily affecting their function and morphology, particularly in synaptic compartments. To better understand the role of mitochondrial impairment in synaptic alterations during the early stages of AD, a morphological investigation was performed by means of electron microscopy in the hippocampus of 3 month-old Tg2576 and transgene-negative littermate mice. In the stratum moleculare of CA1 pyramidal cells (SMCA1) of transgenic animals compared to controls, we found significantly larger and less numerous synapses, with a significantly reduced fraction of the perforated subtype, as well as significantly smaller and more numerous mitochondria. In contrast, no differences between the two groups of mice were found in the inner molecular layer of the dentate gyrus. The reduction of synaptic contacts in SMCA1 indicates a precocious vulnerability of this region, and the synaptic enlargement may reflect a compensating process aimed at maintaining the overall contact density. Accordingly, mitochondrial modifications may represent a plastic reactive phenomenon aimed at sustaining the increased energy needs for synaptic remodeling, since mitochondrial morphology was perfectly preserved and smaller mitochondria are metabolically more efficient. Thus, morphological changes occurring at synaptic level in SMCA1 of 3 month-old Tg2576 mice might reflect a precocious vulnerability associated with a residual plastic reactivity which may slow down functional alterations.

Insulin resistance in Alzheimer's disease

“…Tg2576 exhibit both insulin resistance and altered mitochondrial proteins wherein cognitive enhancement with PPARγ agonism is accompanied by normalization of these proteins critical to energy and metabolism including ATP production, mitochondrial membrane potential and transport dynamics, and redox balance (Denner et al, 2012). These discoveries are consistent with previous reports that mitochondrial dysfunction contributes to cognitive impairment and that both can be ameliorated with PPARγ agonism (Balietti et al, 2013; Gong et al, 2013). Again, these findings dovetail with current thinking that neuroinflammation-induced insulin resistance and mitochondrial dysfunction are interrelated and contribute to the molecular pathogenesis of AD cognitive decline (Bosco et al, 2011).…”

Entorhinal cortical defects in Tg2576 mice are present as early as 2–4 months of age

“…These similarities make the Tg2576 mouse possible to use to clarify mechanisms of EC vulnerability that could be relevant to clinical AD. Another implication is that AD may begin earlier than previously considered, an idea that has been proposed before (Balietti, et al, 2013; Francis, et al, 2012; Jacobsen, et al, 2006; Reiman, et al, 2012). …”

“…There also was a deficit in long-term potentiation of the perforant path projection to the GCs (Jacobsen, et al, 2006). Also, in 3-month-old Tg2576 mice, there was a decrease in synaptic contacts and increase in synaptic length in stratum lacunosum-moleculare of CA1 (Balietti, et al, 2013). These changes could originate in the EC, because the perforant path projection to the DG was affected and there were defects in the area where the perforant path projects to CA1.…”

Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AβPP metabolites in the Tg2576 mouse model of Alzheimer's disease

“…While dendritic pathology was observed in a spatially defined subset of dentate granule cells prior to amyloid deposition in the PDAPP mice (Wu, et al, 2004), Aβ deposition induced progressive degeneration of distinct types of commissural neurons in APP23 mice (Capetillo-Zarate, et al, 2006). It is possible that the spared function seen in LEC compared to hippocampus is due to a selective vulnerability of the latter region to human AβPP and its associated metabolites (Balietti, et al, 2013), or more robust cortical encoding of odors in the face of this pathology.…”