In 1906, Dr. Alzheimer discovered many abnormal clumps and tangled bundles of fibers (now known as Aβ plaques, and hyper-phosphorylated tau tangled protein, respectively) from a deceased brain of a woman who was suffering from memory loss, language problems, and many unpredictable behaviors [1]. Neurons are known to transmit messages from different parts of the brain to muscles and other organs in the body.

Due to the formation of Aβ agglutinated deposit, and their ineffective clearance, forms the pore-like structures in the neurons and cause the synaptic damage, alterations in glutamate receptors, mitochondrial dysfunction, and alterations in signaling pathways [1]. Molecular analysis identifies a number of signaling proteins, like fyn kinase, glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5), which are involved in the neurodegenerative progression of AD [4].

The free-radical theory of aging, though has inspired to use many antioxidants such as alpha-tocopherol, ascorbate and coenzyme-Q to treat the AD, but, in fact, the results are with limited success. In AD, the abnormal aggregations of Aβ and tau proteins are similar to the prion disease, suggesting the formation and spread of corruptive protein templates [5]. Although, the antioxidant cannot reverse the autophagy but can serve in removing the damaged or dysfunctional proteins and organelles to preserve the neuronal function as well as their survival [5].

Senescent cells and their mechanisms of action are still under-studied, but potentially important in the field of neuro-inflammation and subsequent neuro-degeneration. Characterization of cellular process(es) and molecules involved in the senescence of the brain-cells, could focus on some novel therapeutic targets for the prevention of chronic age-related ADs [6]. Here below, we summarize the key players of AD (Figure 1). Further, L-glutamate (or L-aspartate) can mediate acute excite-toxicity in the brain, resulting long-term neurodegenerative processes like AD [7,8].

Underlying mechanisms of developing AD/PDs include mostly Oxidative stress (OS) and/or formation of free radicals/reactive oxygen species (ROS) [9]. Genetic linkage, ageing, stress, pesticides, fungicides/insecticides and SUMOylation process are also considered as causative factors for the onset of PD/AD, and also many other NDDs [10]. Several chemicals used in industry or consumer products including metals (e.g., arsenic, lead, manganese), air pollution, and bacteria-made endotoxins are also believed to cause NDDs, like AD/PD. Besides, some dietary factors (e.g., caffeine, tobacco, dietary antioxidants), as well as lifestyle are linked with the appearance of the diseases like AD and PD [11]. In addition, some stress–related proteins and chaperones have high impact on the pathogenesis of AD and PD [11]. All these pathways interact with other pathways like energetic dysregulation, molecular damage, metabolic change(s), abnormalities in ion homeostasis, and adaptation, ultimate cause the onset of the AD/PD symptoms [12].

AD is also known as Tauopathy as the tau protein gets aggregated and blocks the neural circuit. Whether mitochondrial OS could be an inducer of tauopathy (AD), is a matter of consideration. In fact, OS might occur in the early stages of the disease, even before the tau-agglutination [13]. In the early progression of the disease, mitochondria might not be the only source of ROS, there could be a positive loop between OS generation in any place during the early stages of the disease, which can promote mitochondrial impairment leading to neuronal death. Studies in animal models reveal the importance of antioxidant enzymes in tau pathology. For example, the inhibition of SOD1 and SOD2 leads to increase the tau pathology in mice [13,14], and in a drosophila model [15]. More research should be conducted to confirm the role of mitochondrial dysfunction and OS in tauopathies, which might be the consequence of the age-dependent decrease in antioxidant molecules [16].

Abnormal accumulation of insoluble α-synuclein protein in neurons and glial cells, disturbing normal neural circuit, and resulting in PD, DLB and multiple system atrophy (MSA), altogether called as α-synucleinopathy [17,18,19]. Symptoms of α-synucleinopathy include autonomic nervous system dysfunctions along with many others, like constipation, urinary, sexual dysfunction, and reduced heart rate variability, etc. At the molecular level, this is disease is identified as the mutations in the synuclein (SNCA) gene encoding for α-synuclein. Other genes, PARK, LRRK2 and VPS35, have been found to be associated with variants of autosomal dominant PD, while PARK2, PINK1, and PARK7 cause autosomal recessive PD [20,21].

In the familial PD cases, the individual experiences frequent falls 3 years before the onset of the disease, and at molecular level they express triplication of SNCA, and orthostatic hypotension (OH) with evidence of sympathetic cardiac denervation. The sympathetic cardiac denervation is associated with bi-allelic mutations of PARK2 and the LRRK gene mutations, which showed the symptoms such as constipation, neurogenic bladder and erectile dysfunction, in PD [20]. α-synucleinopathy affects the central autonomic network system and also the preganglionic sympathetic and parasympathetic neurons [22]. The pure autonomic failure (PAF) involves generalized loss of sympatho-adrenomedullary cells, as reflected by a low level of catecholamines (dopamine, norepinephrine, epinephrine) and their byproducts, metanephrines, in blood, whereas in PD and MSA, an organ-selective sympathetic denervation occurs [23].

Mitochondrial dysfunction is also noticed in PD [1]. Besides, the intimate relationships among microglial activation, nitric oxide formation, and neuro-inflammation are also noticed in relation to PDs [1]. In brief, oxidative stress and formation of free radicals/reactive oxygen species, mitochondrial dysfunctions, impaired bioenergetics and DNA damage, neuroinflammatory processes and disruption of cellular/axonal transport are the prime cause for the onset of the PD [4]. Molecular mechanisms of PD formation are shown in Figure 2.

However, having such a fair knowledge of AD/PD we still do not have any cure for those diseases except for some palliative treatments. In that scenario, any other alternative approaches should be welcome. Here we will discuss on cereals and pseudocereals, if they have any merit of cereals and pseudocereals to be considered for that purpose.

These granules contain high fiber which aid in gut health, blood sugar control, and cholesterol reduction, crucial for managing diabetes and cardiovascular -disease. They are also excellent sources of iron, magnesium, calcium, B-vitamins, and Vitamin E, important for overall vitality [24].

The Key Grains, Quinoa, are rich with high protein quality, antioxidants. Amaranth contains complete protein, rich in lysine, squalene, and minerals. Buckwheat is high in rutin, polyphenols, and B-vitamins, while Barley are good in blood-sugar management, potential for anti-cancer properties, and contains antioxidants that helps NDD [25].

Pseudocereals have similar structure as cereal grains and most of the seed components are covered by the endosperm (nutrient store) is encased by the aleurone, which is then enclosed by the testa (seed coat) and the hull (outer husk). However, despite of having enough similarities, not all pseudocereals are placed in the same family as wheat, maize, and rice [26]. Broomcorn millet (Panicum miliaceum L.), canary seed (Phalaris canariensis L.), and teff (Eragrostis teff) are grouped in the Poaceae family (grasses) like wheat, rice, and maize [26]. On the other hand, amaranth (Amaranthus spp.), buckwheat (Fagopyrum esculentum Moench), chia (Salvia hispanica L.), and quinoa (Chenopodium quinoa Willd) are placed in the Amaranthaceae, Polygonaceae, Mint, and Chenopodiaceae family, respectively [27].

In general, all pseudocereals have higher protein and lipid contents and lower carbohydrate content than maize, wheat, and rice. Unlike cereal grains, pseudocereals are rich in bioactive compounds, including dietary fiber, unsaturated fatty acids, lignans, antioxidants, flavonoids, polyphenols, phytosterols, minerals, vitamins, high quality proteins with a balanced aminoacids composition, and essential micronutrients [28,29,30]. Therefore, the high nutrient-rich pseudocereals are found to be associated with health benefits, such as hypolipidemic, anti-inflammatory, anti-hypertensive, anti-cancer, and hepato-protective properties. They also offer benefits against obesity and diabetes [31,32]. Thus, it is hypothesized that the nutrient imbalance created due to carbohydrate-rich cereals (maize/wheat/rice) may be corrected by replacing them with pseudo-cereals in the diets.

Significant emphasis has been placed on the cultivation, research, and new product developments using amaranth, buckwheat, and quinoa [33,34,35]. Therefore, this review first highlights the unique aspects of the chemical composition of amaranth, buckwheat, and quinoa in comparison to that of maize, wheat, and rice are highlighted. Second, the impacts on the compositions of amaranth, buckwheat, and quinoa due to common processing treatments are discussed. Finally, food products that can be formulated using these pseudocereals are covered to inform consumers about potential ways of including pseudocereals in their daily diets while maintaining high nutritive value and sensorial acceptance.

The BBB is highly selective, excluding approximately 98% of small molecules from entering the brain.

In the summary table (Table 2), different Cereals, their major bioactive compounds, and neuro-protective functions are listed.