Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Of all dementia cases, AD accounts for 60–80%. According to the World Alzheimer’s Report in 2021, it reached an estimated 55 million people worldwide in 2020 [1]. AD is the sixth and the fifth leading cause of mortality in the United States, and in people ≥ 65 years old, respectively. In the USA alone, the care costs for the AD reached $355 billion and is expected to reach 1.1$ trillion by 2050 [2].

There are two forms of AD, the sporadic one, and the familial one. The sporadic AD is the common form accounting for 95% of cases. The exact causes and mechanisms of developing AD are not fully understood. However, there are three major hallmarks of the disease: the building up of the incorrectly cleaved β-amyloid protein in the brain which then clumps together forming the plaques between neurons, the accumulation of hyperphosphorylated tau protein within the neurons, and finally neuronal and synaptic loss [3]. To study AD, we need a reliable animal model that mimics the most prevalent sporadic AD. Aluminum-induced AD was shown to be a good animal model.

Aluminum is a well-established neurotoxin that plays a role in the development and progression of AD [4]. Though it is not essential to humans as a nutrient, it is easily ingested through diet and other sources. In people with AD, aluminum accumulates in brain regions such as the frontal cortex and hippocampus [5]. Aluminum can induce β-amyloid aggregation in the brain, which then can lead to the production of β-amyloid plaques. Aluminum could also increase hyperphosphorylation of tau, which leads to neurofibrillary tangles [6]. Aluminum intake causes neurodegeneration through its ability to generate reactive oxygen species and, therefore, develop oxidative stress or induce inflammation in the brain [7].

Though slowing the neurodegeneration has been possible with some treatments such as donepezil, rivastigmine, or memantine, effective treatment in halting these processes or curing the disease has not been found yet [8]. In AD, oxidative stress results from various mechanisms such as mitochondrial dysfunction or accumulation of transition metals. The resulting oxidative stress has been implicated in amyloid-β or tau induced-neurotoxicity. Some studies showed that antioxidants potentially play a role in prevention and treatment of AD (See Fig. A in the supplementary file). Antioxidants have been proposed to combat the oxidative stress of AD [9], [10]. Due to the complex and multifactorial etiology of AD, a single drug hitting a single pathway or target is inefficient. In this context, finding a more effective therapy that can address the multiple mechanisms underlying AD is an urgent need.

Thiophene-based compounds have been reported to possess a wide range of biological activities including antimicrobial [11], anti-mutagenic [12], [13], and anti-proliferative [14], [15], [16], [17], [18], and antioxidant [19], [20], [21] activities. They have been found to inhibit the breakdown of the amyloid precursor protein (APP) into the neurotoxic Aβ39–42 plaques [22], in addition to their antioxidant and anti-inflammatory effects. Therefore, in the present study, we investigated the potential therapeutic effects of a new bithiophene derivative on the AD.