Neurotrophic factors (NTF) are small, versatile proteins that maintain survival and function to specific neuronal populations. In general, the axonal transport of NTF is important as not all of them ...are synthesized at the site of its action. Nerve growth factor (NGF), for instance, is produced in the neocortex and the hippocampus and then retrogradely transported to the cholinergic neurons of the basal forebrain. Neurodegenerative dementias like Alzheimer’s disease (AD) are linked to deficits in axonal transport. Furthermore, they are also associated with imbalanced distribution and dysregulation of NTF. In particular, brain‐derived neurotrophic factor (BDNF) plays a crucial role in cognition, learning and memory formation by modulating synaptic plasticity and is, therefore, a critical molecule in dementia and neurodegenerative diseases. Here, we review the changes of NTF expression and distribution (NGF, BDNF, neurotrophin‐3, neurotrophin‐4/5 and fibroblast growth factor‐2) and their receptors tropomyosin‐related kinase (Trk)A, TrkB, TrkC and p75NTR in AD and AD models. In addition, we focus on the interaction with neuropathological hallmarks Tau/neurofibrillary tangle and amyloid‐β (Abeta)/amyloid plaque pathology and their influence on axonal transport processes in order to unify AD‐specific cholinergic degeneration and Tau and Abeta misfolding through NTF pathophysiology.
Frontotemporal lobar degeneration (FTLD) encompasses a variety of clinicopathologic entities. The antemortem prediction of the underlying pathologic lesions is reputed to be difficult. This study ...sought to characterize correlations between 1) the different clinical variants of primary progressive language and speech disorders and 2) the pathologic diagnosis.
The latter was available for 18 patients having been prospectively monitored in the Lille Memory Clinic (France) between 1993 and 2008.
The patients were diagnosed with progressive anarthria (n = 5), agrammatic progressive aphasia (n = 6), logopenic progressive aphasia (n = 1), progressive jargon aphasia (n = 2), typical semantic dementia (n = 2), and atypical semantic dementia (n = 2). All patients with progressive anarthria had a tau pathology at postmortem evaluation: progressive supranuclear palsy (n = 2), Pick disease (n = 2), and corticobasal degeneration (n = 1). All patients with agrammatic primary progressive aphasia had TDP-43-positive FTLD (FTLD-TDP). The patients with logopenic progressive aphasia and progressive jargon aphasia had Alzheimer disease. Both cases of typical semantic dementia had FTLD-TDP. The patients with atypical semantic dementia had tau pathologies: argyrophilic grain disease and corticobasal degeneration.
The different anatomic distribution of the pathologic lesions could explain these results: opercular and subcortical regions in tau pathologies with progressive anarthria, the left frontotemporal cortex in TDP-43-positive frontotemporal lobar degeneration (FTLD-TDP) with agrammatic progressive aphasia, the bilateral lateral and anterior temporal cortex in FTLD-TDP or argyrophilic grain disease with semantic dementia, and the left parietotemporal cortex in Alzheimer disease with logopenic progressive aphasia or jargon aphasia. These correlations have to be confirmed in larger series.
Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature ...of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Aβ) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood–brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near‐future strategy.
Several lines of evidence indicate that a decrease in the CSF concentration of amyloid beta(42) (Abeta(42)) is a potential biomarker for incident Alzheimer disease. In contrast, studies on plasma ...Abeta(1-40) and Abeta(1-42) peptide levels have yielded contradictory results. Here, we explored the links between incident dementia and plasma Abeta(1-40) and Abeta(1-42) peptide concentrations in the prospective, population-based Three-City (3C) Study. We also assessed the association between plasma concentrations of truncated Abeta (Abeta(n-40) and Abeta(n-42)) and the risk of dementia.
During a subsequent 4-year follow-up period, 257 individuals presented incident dementia from 8,414 participants, and a subcohort of 1,185 individuals without dementia was drawn as a control cohort. Plasma levels of Abeta(1-40), Abeta(1-42), Abeta(n-40), and Abeta(n-42) were measured using an xMAP-based assay technology. The association between plasma Abeta peptide levels and the risk of dementia was assessed using Cox proportional hazard models.
Of the various Abeta variables analyzed, the Abeta(1-42)/Abeta(1-40) and Abeta(n-42)/Abeta(n-40) ratios presented the strongest association with the risk of dementia: people with a high Abeta(1-42)/Abeta(1-40) or Abeta(n-42)/Abeta(n-40) ratio had a lower risk of developing dementia. These associations were restricted to individuals diagnosed at 2 years of follow-up and the Abeta(n-42)/Abeta(n-40) ratio was mainly associated with the risk of mixed/vascular dementia.
Plasma Abeta peptide concentrations and Abeta(1-42)/Abeta(1-40) and Abeta(n-42)/Abeta(n-40) ratios may be useful markers to indicate individuals susceptible to short-term risk of dementia.
Genome-wide association studies (GWAS) have identified a region upstream the BIN1 gene as the most important genetic susceptibility locus in Alzheimer's disease (AD) after APOE. We report that BIN1 ...transcript levels were increased in AD brains and identified a novel 3 bp insertion allele ∼28 kb upstream of BIN1, which increased (i) transcriptional activity in vitro, (ii) BIN1 expression levels in human brain and (iii) AD risk in three independent case-control cohorts (Meta-analysed Odds ratio of 1.20 (1.14-1.26) (P=3.8 × 10(-11))). Interestingly, decreased expression of the Drosophila BIN1 ortholog Amph suppressed Tau-mediated neurotoxicity in three different assays. Accordingly, Tau and BIN1 colocalized and interacted in human neuroblastoma cells and in mouse brain. Finally, the 3 bp insertion was associated with Tau but not Amyloid loads in AD brains. We propose that BIN1 mediates AD risk by modulating Tau pathology.
To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD.
The pathophysiologic significance of AD lesions, namely amyloid plaques ...and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment.
The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively.
NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired.
The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.
Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows ...that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule‐binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R‐t.au isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R‐tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto‐temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.
The aim of the present study was to investigate the relation between neurogenesis, cell cycle reactivation and neuronal death during tau pathology in a novel tau transgenic mouse line THY‐Tau22 with ...two frontotemporal dementia with parkinsonism linked to chromosome‐17 mutations in a human tau isoform. This mouse displays all Alzheimer disease features of neurodegeneration and a broad timely resolution of tau pathology with hyperphosphorylation of tau at younger age (up to 6 months) and abnormal tau phosphorylation and tau aggregation in aged mice (by 10 months). Here, we present a follow‐up of cell cycle markers with aging in control and transgenic mice from different ages. We show that there is an increased neurogenesis during tau hyperphosphorylation and cell cycle events during abnormal tau phosphorylation and tau aggregation preceding neuronal death and neurodegeneration. However, besides phosphorylation, other mechanisms including tau mutations and changes in tau expression and/or splicing may be also involved in these mechanisms of cell cycle reactivation. Altogether, these data suggest that cell cycle events in THY‐Tau22 are resulting from neurogenesis in young animals and cell death in older ones. It suggests that neuronal cell death in such models is much more complex than believed.
Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and ...seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
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