Immununochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

Abstract

BackgroundSeveral findings suggest that the amyloid precursor protein (APP) and the amyloid cascade may play a role in motor neuron disease (MND).ObjectiveConsidering that dementia is one of the most frequent non-motor symptoms in amyotrophic lateral sclerosis (ALS) and that hippocampus is one of the brain areas with greater presence of amyloid-related changes in neurodegenerative diseases, our aim was to analyze the molecular markers of the amyloid cascade of APP in pathology studies of the hippocampus of autopsied patients with ALS and ALS–frontotemporal dementia (FTD).MethodsWe included nine patients with MND and four controls. Immunohistochemical studies and confocal microscopy were used to analyze the expression of APP, TDP-43, pho-TDP-43, Aβ, APP intracellular cytoplasmatic domain (AICD) peptide, Fe65 protein, and pho-TAU in the hippocampus of seven patients with ALS, two patients with ALS–FTD, and four controls. These findings were correlated with clinical data.ResultsPatients displayed increased expression of APP and Aβ peptide. The latter was correlated with cytoplasmic pho-TDP-43 expression. We also found decreased Fe65 expression. A parallel increase in AICD expression was not found. Patients showed increased expression of pho-TAU in the hippocampus. Findings were similar in patients with ALS and those with ALS–FTD, though more marked in the latter group.ConclusionPost-mortem analyses showed that the amyloid cascade is activated in the hippocampus of patients with MND and correlated with cytoplasmic pho-TDP-43 expression. The number of intracellular or extracellular aggregates of Aβ peptides was not significant.

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

“…It is known that a small percentage of ALS patients have ADD pathology [7] and it was shown recently that both amyloid precursor protein (APP) and intracellular Aβ are overexpressed in the hippocampus in ALS compared to CTRL [14]. In animal models of ADD it has been shown that increasing the soluble APP fragment cleaved by α-secretase may improve cognition and rescue long-term potentiation (LTP) [34, 38].…”

Commentary: Immunochemical Markers of the Amyloid Cascade in the Hippocampus in Motor Neuron Diseases

“…In their study (1), the group measured key biomarkers of the amyloid cascade [amyloid precursor protein (APP), transactive response DNA-binding protein 43 (TDP-43), phosphorylated TDP-43 (pho-TDP43), amyloid-beta peptide (Aβ), and amyloid precursor protein-binding protein family B (Fe 65)] immunohistochemically in postmortem samples of the hippocampus of amyotrophic lateral sclerosis (ALS) and ALS–frontotemporal dementia patients. Compared to controls, they report increased levels of APP and Aβ peptide in MND patients; the latter change also correlating with cytoplasmic pho-TDP-43 expression.…”

“…A recent article (1) encourages us to focus on some of the similarities of these diseases by demonstrating that features characteristically associated with AD are also commonly found in MND.…”

“… Numbers refer to the following references: (1) Hinz and Geschwind (2); Aday and Sze (3); (2) Vilemagne et al (4); Gomez-Pinedo et al (1); (3) Ballinger et al (5); Park et al (6); (4) Brandt et al (7); (5) Chen et al (8); Amor et al (9); (6) Atkin and Paulson (10); Jansen et al (11); (7a) Uchihara and Giasson (12); (7b) Helferich et al (13); (8) Kalia and Lang (14); (9) Brandt et al (7); (10) Ticozzi et al (15); (11) Guerrero et al (16) .…”

“…The paper by Gomez-Pinedo et al (1) is a timely reminder that researchers should perhaps not get tied up with the details of these individual diseases that are so important for differential diagnoses. Instead, those seeking to illuminate basic underlying mechanisms might do well to pool data for neurodegenerative diseases in the hope that it will point them in the right direction.…”