Abstract
Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer’s disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed “anti-ageing pathways”, for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.
Highlights
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the progressive loss of cholinergic neurons, leading to the onset of severe behavioral, motor and cognitive impairments
Since extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) containing hyper-phosphorylated tau, are frequently present in the brain of patients with senile dementia, investigators eventually expanded the definition of AD to include those with senile dementia, plaques and tangles (Figure 1) [1]
We have previously shown that a macromolecule found in the synapses interacts with Aβ to form a complex which alters the normal synaptic function in hippocampal neurons [33,34]
Summary
Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the progressive loss of cholinergic neurons, leading to the onset of severe behavioral, motor and cognitive impairments. Deficits in mitochondrial function and increased Aβ accumulation in synapses lead to reduced synaptic activity and consequent neuronal damage. Such synaptic alteration and mitochondrial dysfunction have been observed in many neurodegenerative disorders including AD. Damaged mitochondria, as evidenced by partial or near complete loss of the internal structure and cristae, are abundant and represent a prominent feature in dystrophic neurons in postmortem AD brains [2]. Calcium (Ca2+) mishandling has been reported in peripheral cells isolated from AD patients, with the endoplasmic reticulum (ER) developing calcium overload due to reduced calcium uptake (Figure 1) [3]
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