Targeting mRNA for Alzheimer's and Related Dementias
نویسنده
چکیده
Brain deposition of the amyloid beta-protein (A β ) and tau are characteristic features in Alzheimer's disease (AD). Mutations in the A β precursor protein (APP) and a protease involved in A β production from APP strongly argue for a pathogenic role of A β in AD, while mutations in tau are associated with related disorders collectively called frontotemporal lobar degeneration (FTLD). Despite intense effort, therapeutic strategies that target A β or tau have not yet yielded medications, suggesting that alternative approaches should be pursued. In recent years, our laboratory has studied the role of mRNA in AD and FTLD, specifically those encoding tau and the A β -producing protease BACE1. As many FTLD-causing tau mutations destabilize a hairpin structure that regulates RNA splicing, we have targeted this structure with small molecules, antisense oligonucleotides, and small molecule-antisense conjugates. We have also discovered that microRNA interaction with the 3'-untranslated region of tau regulates tau expression. Regarding BACE1, we found that alternative splicing leads to inactive splice isoforms and antisense oligonucleotides shift splicing toward these inactive isoforms to decrease A β production. In addition, a G-quadruplex structure in the BACE1 mRNA plays a role in splice regulation. The prospects for targeting tau and BACE1 mRNAs as therapeutic strategies will be discussed.
منابع مشابه
Analysis of the incidence and mortality rate of Alzheimer's and other dementias during the last 30 years in Iran
Introduction: Assessing the course of Alzheimer's disease and other dementias is very important due to lack of a definitive treatment, increase in life expectancy, and aging population. This study aimed to investigate the long-term trend in the incidence and mortality rate of Alzheimer's and other dementias in Iran during 1990-2019. Materials and Methods: Age-Standardized Incidence Rate (ASIR) ...
متن کاملKnowledge and Attitudes in Alzheimer's Disease in a Cohort of Older African Americans and Caucasians.
African American participation in Alzheimer's disease (AD) research studies has been historically low. To determine whether older African Americans and Caucasians had different knowledge or attitudes related to AD, we administered the Alzheimer's Disease Knowledge Scale (ADKS) to 67 older African Americans and 140 older caucasians in the greater Atlanta area as well as questions targeting locus...
متن کاملThe Role of Neuroinflammation in Age-Related Dementias.
The most common dementias such as Alzheimer's disease, vascular dementia, Lewy body dementia, and frontotemporal dementia are associated with a decline in cognitive and social abilities. Although the molecular mechanisms of tissue damage in these dementias are not completely understood, these neurodegenerative illnesses share certain alterations such as neuroinflammation and gliosis. Increasing...
متن کاملA life-course approach to the aetiology of late-onset dementias.
Substantial progress has been made in the understanding of the neurobiology of dementias, but comprehensive causal models are not available. Genetic and environmental factors probably interact to determine vulnerability to the dementias. The life-course approach to age-related diseases, when systematically applied to the dementias, provides opportunities to identify the nature and timing of env...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
دوره 2014 شماره
صفحات -
تاریخ انتشار 2014