Alzheimer’s disease (AD) is the most common (60% to 80%) age‐related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells’ life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.

Alzheimer’s disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Aβ immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Na

Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration, including Alzheimer’s disease (AD). A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development. The interaction between mitophagy deficits and Aβ or Tau pathology may form a vicious cycle and cause neuronal damage and death. Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD. Defective mitophagy is a potential target for AD prevention and treatment.

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a tyrosine phosphatase that has been implicated in Alzheimer’s disease (AD), the most common form of dementia, and many other neurological diseases. The protein level and activity of STEP have been found to be elevated in most of these disorders, and specifically in AD as a result of dysregulation of different pathways including PP2B/DARPP32/PP1, PKA as well as impairments of both proteasomal and lysosomal systems. The upregulation in STEP leads to increased binding to, and dephosphorylation of, its substrates which are mainly found to be synaptic plasticity and thus learning and memory related proteins. These proteins include kinases like Fyn, Pyk2, ERK1/2 and both NMDA and AMPA receptor subunits GluN2B and GluA2. The dephosphorylation of these molecules results in inactivation of these kinases and internalization of NMDA and AMPA receptor complexes leading to synapse loss and cognitive impairments. In this study, we aim to review STEP regulation and its implications in AD as well as other neurological disorders and then summarize data on targeting STEP as therapeutic strategy in these diseases.