PROGRESS TOWARDS UNDERSTANDING ALZHEIMER’S DISEASE AND RELATED DEMENTIAS IN THE CONTEXT OF AGING
- Eliezer Masliah, United States of America
Abstract
Abstract Body
Aging is the main risk factor for Alzheimer disease (AD) and other neurodegenerative disorders such as Lewy body dementia (LBD), vascular dementia and frontotemporal dementia (FTD). As a result, close to fifty million people live with dementia over the World. Most efforts indicate that abnormal accumulation and cell to cell propagation of Abeta, Tau, a-synuclein, TDP43 and other proteins in the brain is a key mechanism that explains the neurotoxicity underlying these age-related disorders in the field of neurodegeneration; however very little is known about the molecular mechanisms through which the aging process might lead to selective neurodegeneration in AD and related dementias. Aging is characterized by the progressive accumulation of cellular and molecular damage and represents a delicate balance between resilience, resistance, repair and damage. Mechanisms involved in aging include alterations in DNA repair, proteostasis, inflammation, stem cells turn-around, mitochondrial function and cell senescence among others. The mechanism by which these aging mechanisms are linked to neurodegeneration in AD and related dementias is not understood. How these events -DNA damage, cell senescence, proteostasis and neurodegeneration- influence each other during aging? Is protein aggregation in combination with aging mechanisms responsible for neurodegeneration or are they independent? These are important questions to consider. We review the evidences of the role of aging mechanisms driving protein aggregation and neurodegeneration and address the role of genetic risk factors such as ApoE. Finally, we discuss new therapeutic venues to target aging mechanisms as promising option for future treatment of AD and related dementias.
Aims
We review the evidences of the role of aging mechanisms driving protein aggregation and neurodegeneration and discuss new therapeutic venues to target aging mechanisms.
Methods
The mechanism by which these aging mechanisms are linked to neurodegeneration in AD and related dementias is not understood. How these events -DNA damage, cell senescence, proteostasis and neurodegeneration- influence each other during aging? Is protein aggregation in combination with aging mechanisms responsible for neurodegeneration or are they independent? These are important questions to consider.
Results
Aging is the main risk factor for Alzheimer disease (AD) and other neurodegenerative disorders such as Lewy body dementia (LBD) and vascular dementia and frontotemporal dementia (FTD). As a result, close to fifty million people live with dementia over the World. Most efforts indicate that abnormal accumulation and cell to cell propagation of Abeta, Tau, a-synuclein, TDP43 and other proteins in the brain is a key mechanism that explains the neurotoxicity underlying these age-related disorders in the field of neurodegeneration; however very little is known about the molecular mechanisms through which the aging process might lead to selective neurodegeneration in AD and related dementias. Aging is characterized by the progressive accumulation of cellular and molecular damage and represents a delicate balance between resilience, resistance, repair and damage. Mechanisms involved in aging include alterations in DNA repair, proteostasis, inflammation, stem cells turn-around, mitochondrial function and cell senescence among others.
Conclusions
Understanding the role of aging mechanisms in AD is critical at developing novel therapeuticals combining anti-aging apporaches with drugs targeting the proteinopathy.