Genome instability in Alzheimer disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.

Keywords: Alzheimer’s disease; DNA damage; DNA repair.

Figure 1. Pathways of DNA repair

Genetic or environmental factors cause several types of DNA damage, including bulky adducts, abasic sites, DNA SSBs, DSBs, base alkylation, methylation, base mismatches, insertions and deletions. These DNA lesions may contribute to neuronal loss and AD progression. The major DNA repair pathways are base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), double strand break repair (DSBR) and direct reversal. DSBR includes homologous recombination (HR) and non-homologous end joining (NHEJ).

Figure 2. How DNA repair plays a role in sporadic Alzheimer’s disease

Since there are several different hypotheses about the origins of AD, we have used an “X” to represent the initiation of AD. Loss of DNA repair may exacerbate Alzheimer’s disease through multiple pathways including changes in vascular factors, glutamate signaling, nuclear and mitochondria DNA damage and repair pathways.