**1. Introduction**

Major clinical hallmarks of Alzheimer's disease (AD) are memory loss and cognitive impairment. Pathologically, AD is manifested by overproduction of toxic intracellular β-amyloid (Aβ) oligomers, deposited into extracellular senile plaques (SPs), and by hyperphosphorylation of

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tau protein deposited into neurofibrillary tangles (NFTs). Aβ is processed by the γ-secretase complex, where the most important component is presenilin [1]. There are two major types of AD: early-onset AD (EOAD), often linked with familial AD (FAD), and late-onset AD (LOAD), linked with sporadic AD (SAD). Familial EOAD represents 5–10% of all cases of AD and is associated with mutations in *PSEN1* encoding presenilin (PS1), *PSEN2* encoding presenilin 2 (PS2), and *APP* encoding amyloid β protein precursor (APP) [2, 3]. Overall, presenilins and APP mutations directly cause a production of toxic assemblies of oligomerized Aβ, followed by a formation of senile plaques [4]. Toxic Aβ forms induce apoptosis, oxidative stress, unfolded protein stress response, inflammation, or disturbances in calcium signalling, of which many are present in pathological ageing or in Alzheimer's disease.

Normal ageing results from natural maturational processes, whereas pathological ageing is related to non-normative factors such as disease or trauma to the brain. Ageing disproportionately affects frontal lobes [5]. Substantial overlap between ageing and neurodegeneration was demonstrated in several brain autopsy studies of aged people with no record of neurological diseases. These reports showed the presence of amyloid plaques, neurofibrillary tangles, Lewy bodies, inclusions of TAR DNA-binding protein 43 (TDP-43), synaptic dystrophy, and loss of neurons in most of ageing brains [6, 7]. However, unlike AD, pathological ageing usually lacks cognitive impairment despite similar senile plaque [8]. It was found that oxidative stress, commonly accompanying both ageing and AD, causes pathogenic conformational change of PS1 in neurons in vitro, which was followed by an increased ratio of Aβ42/40. It was further concluded that this conformational shift and deregulation of PS1 precedes Aβ deposition in pathological ageing [9]. These data demonstrated a direct connection between presenilins and PA. Presenilins contribute to brain pathology not only by deposition of toxic Aβ. Both PS1 and PS2 have been found to be involved in the regulation of apoptosis in neurons induced by trophic withdrawal or Aβ and via Jun Kinase pathway, respectively [10]. What is more, the role of presenilins in the progression of AD and PA is underlined by their numerous functions in the adult cerebral cortex functions, including maintenance of synaptic plasticity, long-term memory, and neuronal survival, which are critical for normal ageing, healthy brain, and cognitive ability [11].

Summarizing, presenilin functions can be controlled at different cellular levels, that is, (1) gene architecture, together with the influence of damaging genetic variants, in *PSEN1* and *PSEN2*, (2) gene expression, together with corresponding regulatory protein networks, (3) protein structure with its enzymatic activity, controlled by the assembly of the γ-secretase complex with accompanying partners and by post-translational modifications (phosphorylation and ubiquitination), (4) quantity, quality and availability of numerous substrates of presenilins and finally (5) by the interaction with molecular partners involved in numerous biological processes. Hereby, we highlighted that presenilins can determine different physiological and pathological processes by the interplay with diverse signal transduction pathways and by processing of various substrates. Generally, presenilins form a signalling network, which is critical for both AD and PA. Therefore, we present below molecular players that might affect biological functions of presenilins forming together so-called presenilin interactome.
