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.

Introduction

The past few years have witnessed considerable progress in the fight against Alzheimer's disease (AD), with the introduction of the revised clinical [1] and neuropathological [2] criteria for the diagnosis of AD, identification of new biomarkers [3], [4], [5], better characterization of the poly-genetic aspects of AD [6], [7], and a more clear understanding of the contribution of neurotoxic aggregates of amyloid β (Aβ) [8], [9], [10] and microtubule associated protein τ (Tau) [11], [12], to the pathogenesis of neurodegeneration in AD. Likewise, in disorders with parkinsonism and dementia such as Parkinson's disease (PD), PD with dementia (PDD) and dementia with Lewy bodies (DLB) (jointly denominated Lewy body disease [LBD]) [13] dramatic progress has been made in identifying new genes involved in familial [14] and sporadic [15] forms, several of them possibly converging on the α-synuclein (α-syn) pathway [16], [17].

In 2013 an estimated 5.2 million Americans of all ages have AD and 1 million have PD [18]. This year an estimated 450,000 people in the US will die with AD, making AD the sixth-leading cause of death in the US [18]. Without a cure, the number of cases of AD, as defined by the 1984 and DSM-IV criteria, will double by the year 2050, with western states experiencing the highest rates [18]. The new criteria published in 2011 proposed three stages of the disease, namely preclinical AD, mild cognitive impairment (MCI) due to AD, and dementia due to AD [1]. The 2011 criteria proposes that AD begins before the development of symptoms and that new positron emission tomography (PET) and cerebral spinal cord fluid (CSF) biomarkers are able to identify brain alterations before the onset neurological alterations [1]. However, the predictive value of such biomarkers is not yet proven in sporadic preclinical cases [19]. If AD can be detected earlier, as defined by the 2011 criteria, the number of people reported to have AD will be much larger than 5 million.

In 2011, a workgroup of experts was organized to revise the 1997 neuropathological criteria for the diagnosis of AD and related disorders [2]. The 1997 criteria required a history of dementia [20], while the new criteria disentangle the clinico-pathologic term “Alzheimer's disease” from AD neuropathologic change [2]. Using the new criteria, AD neuropathologic change would be ranked along three parameters (Amyloid, Braak, CERAD) to obtain an “ABC score”. For this purpose a modified version of Thal phases of Aβ plaque accumulation was proposed [21], adapted to a four-point scale, continued use of the staging scheme for neurofibrillary tangles as described by Braak [22], reduced to four stages that improves inter-rater reliability, and continued use of CERAD protocol for neuritic plaque scoring [23]. The new criteria provided guidance on clinico-pathologic correlations for pathologists reporting autopsy findings based on the literature and analysis of the National Alzheimer's Coordinating Center (NACC) database. The new criteria also emphasized the importance of assessing non-AD brain lesions in recognition of commonly co-morbid conditions in cognitively impaired elderly. Among the co-morbid conditions, synucleinopathies such as PD, PDD and DLB, are important given that over 75% of patients with AD display LB's in the amygdala [24], [25] and about 25% of patients with AD develop parkinsonism [26].

The main purpose of this manuscript is to review evidence supporting the synapse failure hypothesis of AD and LDB and the role of Aβ, α-syn, and Tau accumulation in the pathogenesis of this process. We conclude that synaptic dysfunction occurs early, followed by pre-synaptic and spine loss, axonal dystrophy and eventually neuronal loss. We focus on synapses because Aβ is released at the synaptic terminal [27] and α-syn localizes to the synaptic vesicles [28] where they can effect synaptic transmission. However, a number of other cellular substrates play an equal important role (e.g., neuro-inflammation, vascular, glial) and deserve close consideration. For example, a recent GWAS study highlighted the association of AD with innate immune response [29], [30], [31], [32], [33].