Abstract
Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.
Highlights
Alzheimer’s disease (AD), the most common form of dementia, affects 44 million people worldwide [1]
Two of the main neuropathological characteristics of AD are the accumulation of amyloid plaques and neurofibrillary tangles (NFTs)
AD has been proposed to be a disease with a complex etiology in which these earlier alterations participate in the appearance and accumulation of plaques and tangles, which in turn aggravate the earlier pathological events in a positive feedforward loop
Summary
Alzheimer’s disease (AD), the most common form of dementia, affects 44 million people worldwide [1]. These alterations include neuroinflammation, cellular senescence, altered proteostasis, oxidative stress, and reduced neurogenesis [11,12,13,14,15]. This review summarizes the implication of these pathways and their interplay on the most relevant aspects of this disease, including amyloid plaques, NFTs, cholinergic degeneration, oxidative stress, mitochondrial dysfunction, disturbed energy metabolism, cellular senescence, neuroinflammation, altered neurogenesis, and impaired neurotransmission. We have emphasized the alterations of their function in different aspects of AD as well as their interactions, especially in amyloid plaque and NFT formation, oxidative stress, energy metabolism, neuroinflammation, neurotransmitter release, and synaptic dysfunction Among these pathways are those controlled by the Dual Specificity Tyrosine-Regulated Protein Kinase 1 (DYRK1A), the Regulator of Calcineurin (RCAN1), neurotrophins, and the Mammalian Target of Rapamycin (mTOR).
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