Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease.

Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aß) and phosphorylated and truncated tau proteins. Aß deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aß clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aß aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.

Molecular Processing of Tau Protein in Progressive Supranuclear Palsy: Neuronal and Glial Degeneration.

BACKGROUND: Alzheimer's disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. OBJECTIVE: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. METHODS: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. RESULTS: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. CONCLUSION: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP.

Whole sequence of the mitochondrial DNA genome of Kearns Sayre Syndrome patients: Identification of deletions and variants.

Mitochondria both produce the energy of the cell as ATP via respiration and regulate cellular metabolism. Accordingly, any deletion or mutation in the mitochondrial DNA (mtDNA) may result in a disease. One of these diseases is Kearns Sayre syndrome (KSS), described for the first time in 1958, where different large-scale deletions of different sizes and at different positions have been reported in the mitochondrial genome of patients with similar clinical symptoms. In this study, sequences of the mitochondrial genome of three patients with clinic features of KSS were analyzed. Our results revealed the position, heteroplasmy percentage, size of deletions, and their haplogroups. Two patients contained deletions reported previously and one patient showed a new deletion not reported previously. These results display for the first time a systematic analysis of mtDNA variants in the whole mtDNA genome of patients with KSS to help to understand their association with the disease.

Phylogenetic analysis of mitochondrial DNA in a patient with Kearns-Sayre syndrome containing a novel 7629-bp deletion.

Mitochondrial DNA mutations have been associated with different illnesses in humans, such as Kearns-Sayre syndrome (KSS), which is related to deletions of different sizes and positions among patients. Here, we report a Mexican patient with typical features of KSS containing a novel deletion of 7629 bp in size with 85% heteroplasmy, which has not been previously reported. Sequence analysis revealed 3-bp perfect short direct repeats flanking the deletion region, in addition to 7-bp imperfect direct repeats within 9-10 bp. Furthermore, sequencing, alignment and phylogenetic analysis of the hypervariable region revealed that the patient may belong to a founder Native American haplogroup C4c.