Elsevier

Neuroscience

Volume 251, 22 October 2013, Pages 51-65
Neuroscience

Review
Synaptic changes in Alzheimer’s disease and its models

https://doi.org/10.1016/j.neuroscience.2012.05.050Get rights and content

Abstract

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by a progressive loss of cognition and the presence of two hallmark lesions, senile plaques (SP) and neurofibrillary tangles (NFT), which result from the accumulation and deposition of the β-amyloid peptide (Aβ) and the aggregation of hyperphosphorylated tau protein, respectively. Initially, it was thought that Aβ fibrils, which make up SP, were the root cause of the massive neurodegeneration usual found in AD brains. Over time, the longstanding emphasis on fibrillar Aβ deposits and neuronal death slowly gave way to a new paradigm involving soluble oligomeric forms of Aβ, which play a prominent role in triggering the cognitive deficits by specifically targeting synapses and disrupting synaptic signaling pathways. While this paradigm is widely accepted today in the AD field, the molecular details have not been fully elucidated. In this review, we address some of the important evidence, which has led to the Aβ oligomer-centric hypothesis as well as some of the key findings concerning the effects of Aβ oligomers on synapses at a morphological and functional level. Understanding how Aβ oligomers target synapses provides an important framework for ongoing AD research, which can lead to the development of successful therapeutic strategies designed to alter or perhaps reverse the course of the disease.

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.

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