ReviewSynaptic changes in Alzheimer’s disease and its models
Highlights
► Alzheimer’s disease is the result of synaptic dysfunction and neuronal loss. ► Mouse models of AD recapitulate the synaptic dysfunction phenotype. ► Memory deficits are associated with the loss of dendritic spine numbers/morphology. ► Aβ targets and destroys dendritic spines by hijacking cytoskeletal signaling pathways. ► Dendritic spine pathologies in mouse models are reversible by a variety of treatments.
Section snippets
Alzheimer’s disease (AD)
Alzheimer’s disease (AD), the most common dementing disorder in the elderly, is characterized pathologically by the presence of senile plaques (SP) and neurofibrillary tangles (NFT), and by a massive loss of neurons and synapses in the brain. The pathogenesis of AD remains unclear to this day. However, the beta-amyloid (Aβ) peptide, derived from the cleavage of the amyloid precursor protein (APP), has been hypothesized to be a key player and may potentially play a causal role in the disease
Synaptic dysfunction in AD patients
Abnormalities in synapses from AD brain tissue were first described more than four decades ago by Gonatas and colleagues (Gonatas et al., 1967). Since then, there has been a wealth of studies that have reinforced the notion that the loss of synaptic function is a key characteristic of AD. Quantitative ultrastructural and immunohistochemical postmortem studies from Masliah (Masliah et al., 1989, Masliah et al., 1993, Terry et al., 1991, Masliah and Terry, 1993); and Scheff (Scheff and Price, 1993
Dendritic spine morphology and structure
Originally observed and described by Ramon y Cajal in the late 19th century (Ramon y Cajal, 1888), dendritic spines are now recognized as specialized anatomical structures on neuronal cells that serve as the postsynaptic component for the vast majority of central nervous system excitatory synapses. Dendritic spines come in several shapes and sizes but most of them are composed of a variably shaped bulbous tip (∼0.5–2.0 μm in diameter and 0.01–0.8 μm3 in volume), called the spine “head” connected
Dendritic spine changes in AD mouse models
The study of AD was advanced when Games and colleagues published the first mouse model to recapitulate some of the AD hallmarks (Games et al., 1995). The mouse was engineered to overexpress the human APP gene containing a valine to phenylalanine substitution at amino acid 717 (V717F) under the control of a neuron-specific promoter (PDAPP). These mice progressively develop many of the phenotypes typically associated with AD, including numerous extracellular thioflavin S-positive Aβ deposits,
Electrophysiological and behavioral changes
Increases in the efficacy of synaptic transmission in excitatory synapses, usually referred to as LTP, are thought to be one of the basic mechanisms underlying learning and memory (Malenka and Nicoll, 1999). This process is calcium and NMDA receptor-dependent and consists of an increase in the glutamatergic synaptic strength by insertion of AMPAR at the surface of the synapse (Malenka and Bear, 2004, Whitlock et al., 2006). It is often thought that structural remodeling of spine synapses
β-Amyloid (Aβ) interactions with dendritic spines
One question that has stumped researchers is how Aβ oligomers target neurons, and just as importantly, which memory-related pathways are dysregulated by Aβ. One interesting hypothesis that has been proposed is that Aβ directly acts as a pathogenic ligand, targeting dendritic spines, perhaps through one or more putative receptors, thereby disrupting signaling pathways at sites critical to memory formation. The idea of a putative Aβ receptor is one that has garnered a number of advocates over the
Dendritic spine actin cytoskeletal alterations
The acute effects of Aβ oligomers on normal synaptic function, whether through induction of LTD or blockage of LTP have been well established and appear to directly translate into changes in synaptic morphology resulting in dendritic spine shrinkage or collapse (Matsuzaki et al., 2004, Nagerl et al., 2004, Zhou et al., 2004, Bastrikova et al., 2008) as a result of F-actin remodeling (Selkoe, 2008). In LTD for example, the shrinkage of dendritic spines occurs through the cofilin-mediated
Therapeutic approaches to reversing spine pathology
The use of primary neuronal cultures and AD mouse models has enabled researchers to examine the importance of specific pathways or proteins in the rescue of dendritic spine loss. In this section we will examine treatments that rescue the spine deficits that we have described above.
We will begin by describing a series of reports that examine the regulation of NMDA receptors by Aβ oligomers and how these changes can be prevented. Exposure of hippocampal primary cultures to Aβ oligomers targets
Conclusions
Decreases in the density of dendritic spines and alterations in their morphology occur in Alzheimer’s disease and are seen in animals models of Alzheimer’s disease that overexpress mutant human APP. It is less clear that the alterations in tau seen in models of the tauopathies show as consistent alterations in these structures. Similar alterations are seen in primary neuronal cell cultures treated with Aβ. These changes appear to be reversible by a large variety of treatments or simply by the
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These authors contributed equally to this paper.