Aggregates of dysfunctional proteins and peptides in or between brain neurons are key neuropathological features of dementias and are believed to directly cause or substantially contribute to the development of these diseases. Fundamental parts of the mechanisms underlying the dysregulation of proteins in Alzheimer's disease, frontotemporal dementia and other dementing disorders are now well characterized, mainly due to the discovery of genes causing dominantly inherited disease forms.

Alzheimer's disease (AD), the most common form of dementia, is characterized by two types of brain lesions, referred to as senile plaques and neurofibrillary tangles. A series of endoproteolytic cleavages of amyloid precursor protein (APP) controlled by α-, β-, and γ-secretases leads to a formation of non-amyloidogenic (α-secretase pathway) and amyloidogenic (β-secretase pathway) products which are essential for neurodegeneration. According to "the amyloid hypothesis", the accumulation of amyloid β (Aβ) peptides in the brain is a primary event in the pathogenesis of AD. One of the strong pieces of evidence supporting this hypothesis was the identification of pathogenic mutations within APP, Presenilin 1 and Presenilin 2 genes responsible for familial autosomal dominant cases of AD. The mutations affect APP processing causing overproduction of Aβ42 alloform. Over 85% of patients can be considered as sporadic late onset AD with more complex mode of inheritance and a multifactoral etiology. Aβ aggregation in sporadic AD may be induced by yet unknown post-translational modifications of Aβ and/ or by altered mechanism of Aβ clearance from the cell. Biochemical studies confirm that changes in cholesterol metabolism in neurons may underlie the pathological processes in AD. The APOE*4 allele of Apolipoprotein E gene is a major risk factor in sporadic late onset AD.

Frontotemporal dementia (FTD) is characterized by atrophy of the frontal and temporal lobes of cortex and an abundant pathology of tau protein. Tau promotes assembly of microtubules and it is involved in neurite outgrowth, axonal transport and cell polarity. In human brain, three isoforms of 3R-tau type and three isoforms of 4R-tau type are produced in ratio 1:1 by alternative splicing of the Microtubule Associated Protein Tau (MAPT) gene. So far, over 30 pathogenic mutations within the MAPT gene have been found in families with autosomal dominantly inherited forms of FTD with parkinsonism linked to chromosome 17 (FTDP-17). Most of the mutations change the biochemical properties of the protein and/ or alter the regulation of exon 10 alternative splicing leading to disturbances in 4R-tau isoforms production. Moreover, a small subset of ubiquitin-positive FTDP-17 cases can be explained by mutations in the Progranulin (PGRN) gene. A variety of pathogenic consequences of the MAPT and PRGN gene defects could explain the wide range of clinical features observed in different families with FTDP-17.

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/12002 must be provided.