Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease

Abstract

Considerable progress has been made in the past few years in the fight against Alzheimer's disease (AD) and Parkinson's disease (PD). Neuropathological studies in human brains and experimental in vivo and in vitro models support the notion that synapses are affected even at the earliest stages of the neurodegenerative process. The objective of this manuscript is to review some of the mechanisms of synaptic damage in AD and PD. Some lines of evidence support the notion that oligomeric neurotoxic species of amyloid β, α-synuclein, and Tau might contribute to the pathogenesis of synaptic failure at early stages of the diseases. The mechanisms leading to synaptic damage by oligomers might involve dysregulation of glutamate receptors and scaffold molecules that results in alterations in the axonal transport of synaptic vesicles and mitochondria that later on lead to dendritic and spine alterations, axonal dystrophy, and eventually neuronal loss. However, while some studies support a role of oligomers, there is an ongoing debate as to the exact nature of the toxic species. Given the efforts toward earlier clinical and preclinical diagnosis of these disorders, understanding the molecular and cellular mechanisms of synaptic degeneration is crucial toward developing specific biomarkers and new therapies targeting the synaptic apparatus of vulnerable neurons.

Keywords: Alzheimer's disease; Lewy body disease; Synapse; Synuclein; Tau.

Figure 1

Schematic diagram showing the processing of APP, the formation of Aβ oligomers, and its interaction with Tau in the mechanisms of synapse loss. A) APP is cleaved by β and γ-secretases to form sAPPβ. Monomeric Aβ42 can form Aβ oligomers that can be cleared by ApoE and proteases such as neprilysin and IDE. Both Aβ monomers and oligomers progress to fibrils and plaques, while Aβ oligomers interact with surface receptors that in turn activate various kinases to alter Tau, leading to loss of axonal transport of neurotrophic factors and impaired mitochondrial function, culminating in neurotoxicity. B) Aβ production is dependent on both Aβ clearance, aggregation and synthesis.

Figure 2

Schematic representation of progression of the mechanisms of synaptic damage in AD and synucleinopathies. At the earliest stages, oligomers interfere with the transport of synaptic vesicle proteins and glutamate receptors resulting in functional deficits that are potentially reversible. Later on signaling pathways and Tau are engage in association with axonal transport defects of trophic factors and mitochondria that in turn lead to synaptic loss and oxidative stress. This is followed by axonal alterations and eventually neuronal loss, resulting in irreversible damage different neurotoxic insults, their effect on neuronal function, and stage with in the disease progression.

Figure 3

Role of α-syn in the mechanisms of synapse loss in Lewy body disease. A) Neurotoxic events and genetic predisposition lead to α-syn misfolding and aggregation that in turn leads to synaptic damage and ultimately neurodegeneration of dopaminergic and non-dopaminergic circuits. B) Increased synthesis and aggregation, and/or decreased clearance of α-syn leads to α-syn accumulation causing toxicity via oligomers and propagation of the toxic species resulting in in axonal and synaptic damage.