Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies

Abstract

TAR-DNA-binding protein 43 (TDP-43) has been identified as a major component protein of ubiquitin-positive inclusions in brains from patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. To obtain the precise prevalence of TDP-43 pathology in neurodegenerative disorders, we examined brains from patients with tauopathies and synucleinopathies as well as FTLD-U using immunohistochemical analysis. Consequently, TDP-43-positive inclusions within neurons and oligodendroglia were found in brains from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) in addition to FTLD-U, but not with Parkinson's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration or FTDP-17. The amygdala and hippocampus that were vulnerable to tau or α-synuclein pathology demonstrated more severe TDP-43 pathology in AD and DLB cases than in FTLD-U cases. In contrast, in the frontal cortex and basal ganglia that were vulnerable to TDP-43 pathology in FTLD-U, TDP-43 pathology was not observed in AD and DLB cases. Thus, the neuroanatomical distribution of TDP-43 pathology in AD and DLB cases was obviously different from that in FTLD-U cases. Furthermore, a subset of TDP-43-positive inclusions co-existed with neurofibrillary tangles (NFTs) or Lewy bodies (LBs) in the same neurons. Upon double-immunofluorescent labeling analysis, TDP-43 was hardly superimposed with tau, while TDP-43 was partially superimposed with α-synuclein, suggesting that neither NFTs nor LBs themselves show TDP-43 immunoreactivity and that TDP-43 pathology found in this study may be related in some way to AD and LB pathology. This study will provide a more in-depth understanding of the various pathogenic pathways leading to neurodegenerative disorders.

Introduction

Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia in populations below the age of 65 years (Bian and Grossman, 2007) and is characterized by behavior and personality changes, language impairment, and cognitive decline. FTLD consists of three clinical subtypes including frontotemporal dementia (FTD), progressive non-fluent aphasia (PA), and semantic dementia (SD). FTD is further classified into the frontal lobe degeneration type, Pick type, and motor neuron disease type (Neary et al., 1998). Additionally, FTLD has at least three neuropathological subtypes, including FTLD with tau-positive pathology (FTLD-τ), FTLD with ubiquitin-positive tau-negative inclusions (FTLD-U), and FTLD with no identifiable intracellular inclusions (also termed dementia lacking distinctive histopathology; DLDH) based on the immunohistochemical profile of intracellular inclusions (Neary et al., 2005).

On the other hand, a substantial proportion of patients with amyotrophic lateral sclerosis (ALS) also present both cognitive and behavior impairment (Murphy et al., 2007). Moreover, the main pathological hallmark of ALS with dementia (also termed dementia with motor neuron disease, D-MND) is an intraneuronal ubiquitin-only-positive inclusion that is observed in hippocampal and neocortical neurons as well as motor neurons in the brainstem and spinal cord (Wightman et al., 1992), suggesting a link between FTLD-U and ALS. Although most patients with FTLD or ALS are sporadic, a substantial proportion of the patients have a clear-cut family history of either FTD or ALS. Indeed, genome-wide linkage analyses have revealed several genetic loci and mutations in specific genes associated with FTLD and/or ALS such as mutations in charged multivesicular body protein 2B (CHMP2B) in families with FTD linked to chromosome 3 (FTD-3) (Skibinski et al., 2005), ALS-FTD linked to chromosome 9q21–q22 (Hosler et al., 2000), and mutations in valosin-containing protein (VCP) in families with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) linked to chromosome 9p (Watts et al., 2004), as well as mutations in microtubule-associated protein tau (MAPT) (Hutton et al., 1998, Poorkaj et al., 1998, Spillantini et al., 1998) and progranulin (PGRN) (Baker et al., 2006, Cruts et al., 2006) in families with FTD with parkinsonism linked to chromosome 17 (FTDP-17). Of these disorders involving pathogenic mutations, IBMPFD linked to VCP, FTDP-17 linked to PGRN, and ALS linked to CHMP2B all show ubiquitin-positive tau-negative pathology (Baker et al., 2006, Cruts et al., 2006, Forman et al., 2006, Parkinson et al., 2006), providing further support for a possible association between FTLD-U and ALS. Consistent with this hypothesis, TAR-DNA-binding protein 43 (TDP-43) has been recently identified as a major component of ubiquitin-positive inclusions in brains of patients with FTLD-U or ALS (Arai et al., 2006, Neumann et al., 2006), and the concept that FTLD-U and ALS might be classified into a single disease spectrum termed TDP-43 proteinopathy has been proposed (Arai et al., 2006, Davidson et al., 2007, Neumann et al., 2006).

In addition to ubiquitin-positive inclusions, other inclusions consisting of different aggregated proteins are found in brains from patients with several neurodegenerative disorders, such as neurofibrillary tangle (NFT) in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), pre-tangle (PT) in corticobasal degeneration (CBD), Pick body (PB) in Pick's disease (PiD), and Lewy body (LB) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Biochemical and genetic analyses have provided us with advanced understanding about major components of these protein aggregations such as tau in NFT, PT, or PB and α-synuclein in LB. Therefore, these neurodegenerative disorders have been recently classified into two groups, tauopathies and synucleopathies. However, clinico-pathological overlapping is frequently observed across both groups (Lee et al., 2004), suggesting that there may be an interaction between tau and α-synuclein or a common pathogenic pathway between tauopathies and synucleopathies.

In this study, to obtain the precise prevalence of TDP-43-positive inclusions in neurodegenerative disorders and clarify the relationship of TDP-43 with two other neurodegenerative disease-associated proteins, tau and α-synuclein, we investigated TDP-43 pathology in tauopathies and synucleopathies as well as FTLD-U using immunohistochemical analysis. Here, we describe that TDP-43 pathology was observed in the brains of AD and DLB patients as well as FTLD-U patients and that TDP-43-positive inclusions occasionally co-existed with tau-positive NFTs or α-synuclein-positive LBs in the same neurons, which might suggest a possible relationship between TDP-43, tau, and Lewy pathology.