Americans aged 65 and older suffering from Alzheimer’s disease (AD) are estimated to be about 6.5 million [1]. By the end of 2040, U.S. population with dementia might reach 11.2 million of cases, around 70% higher than 2022 (Fig. 1). AD is a neurodegenerative disorder characterized by progressive cognitive impairment with loss of memory and behavioural difficulties [1]. Well-known pathological markers found in AD patients are extracellular aggregates of beta-amyloid (Aβ) and intracellular hyperphosphorylated tau (hyp-tau) deposits. The former lead to the formation of senile plaques, while the latter aggregates are self-organized structures namely tangles, which impair the tau function as stabilizer for microtubules and alter the motor protein-mediated transport [2]. Recently, mechanotransduction has been related to pathological changes occurring during AD progression. Mechanotransduction is the process that converts mechanical stimuli from the extracellular matrix into biochemical signals inside the cell, with consequences on cell structure, gene expression and physiological functions [3]. The extracellular stimuli are propagated into the nucleus via sequential interactions of integrins, F-actins, the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex and the nuclear lamina (Fig. 2) [4,5,6]. Integrins are heterodimeric transmembrane receptors, which mediate the ECM-cytoskeleton microfilaments connection. The ECM-cytoskeleton link is further strengthened by the presence of other key cytosolic proteins, such as talin and vinculin [7]. The cytoskeleton proximal to the plasma membrane is predominantly composed by F-actin microfilaments and supports the cell structure [7]. F-actin microfilaments are connected to the nuclear lamina by the LINC complex, consisting of nesprins and SUN proteins [5]. Nesprin 1 and nesprin 2 pass through outer nuclear membrane, connecting F-actin to the SUN1, a protein crossing the inner nuclear envelope [4, 5]. Among the SUN protein family, SUN1 was reported to interact with the nuclear lamina [4, 5]. As previously stated, this complex transduction network may have a role in AD.

Estimation of U.S. population with Alzheimer’s disease in the next decades. The data are based on a study conducted by the Alzheimer’s Association [1, 8]

Force transmission pathway from the ECM to the nuclear lamina. Extracellular matrix interacts with integrins that transduce the mechanical stimuli to the cytosolic F-actin through the plasma membrane. The F-actin microfilaments are connected to the nuclear lamina by the LINC complex, consisting of nesprins and SUN proteins. SUN proteins are directly connected to the nuclear lamina

Even tough specific aspects of mechanotransduction in neurons have already been discussed, to the best of our knowledge, there is no work summarizing the entire pathway from ECM to synapse response. To fill this gap, this review summarizes evidence dealing with this hypothesis and explains how the extracellular matrix affects the nuclear lamina and how this may be associated to the impaired synaptic activity affecting AD neurons. To this end, we firstly analyzed literature highlighting the alteration of single components of the mechanotransduction pathway. In particular, we report the changes in ECM, nuclear lamina, nuclear transport and synaptic activity in AD. We then discuss incisive connections between the single players, defining a hypothetic mechanism of the mechanotransduction-driven disease progression.

ECM composition is tissue-dependent and collagens, elastin, proteoglycans and glycosaminoglycans (GAGs) are some of the most characterizing fibrous proteins [9]. ECM has a dynamic structure since its organization undergoes repeated modifications in correlation with aging and pathology progression [9, 10]. The extracellular matrix guarantees the ideal environment for cell support, growth, migration, differentiation and survival [11,12,13]. Focusing on the brain, ECM behaves as a three-dimensional network for many physiological processes, including development regulation, tissue homeostasis and neuronal plasticity. ECM structure occupies around 20% of the brain adult volume [14]. The composition reported by Sethi et al. [15] and Hall et al. [9] showed high percentages of proteoglycans and hyaluronan, while a minor proportion is taken by collagens and fibronectin. Using cortex and cerebellum of 24-month-old mice compared to the 4-month-old mice, hyaluronic acid concentration was altered in aging and neurodegenerative diseases [9, 10, 16]. Furthermore, some proteoglycans such as decorin, chondrotin sulfate and heparin sulfate proteoglycans have some effects on neurofibrillary tangles formation and beta amyloid interactions, the two primary elements characterizing Alzheimer’s disease [17,18,19,20,21]. Changes in ECM composition lead to a modification of the mechanical properties (i.e. shear elasticity (μ)) and may be correlated to aging and AD onset. Nowadays the literature on the AD-related ECM features is still dependent on the techniques used. Hiscox et al. [22] used magnetic resonance elastography (MRE) to study the ECM stiffness of 12 healthy young subjects with an age between 19 and 30 (mean age 25.2 ± 3.0 years), gaining a shear stiffness physiological value in the hippocampal region of 2.89 ± 0.32 kPa. According to MRE technique, the ECM softens during aging, resulting in an annual stiffness decrease rate of ∼0.8% (0.015 kPa per year) (Table 1) [22,23,24,25,26,27,28]. MRE is a non-invasive technique, which combines traditional magnetic resonance imaging with acoustic waves, allowing to evaluate viscoelastic properties of soft tissues [29]. However, its resolution is affected by the long time for acquisition (minutes), enlarging the risk of possible patients’ head movements [30]. In line with this, Kalra et al. [28] combined MRE with diffusion tensor imaging (DTI) to deepen the local and directional dependency of brain tissue stiffness and confirmed the stiffness decrement. An anisotropic approach in the brain stiffness study was applied to find more details about shear stress vector orientation on different planes in space. This study reported a decrease in ECM stiffness, in accordance with the results obtained applying only MRE. In contrast to MRE and DTI results, atomic force microscopy (AFM) and indentation techniques showed stiffness increment of ∼20–150% with aging [31, 32]. Unlike MRE and DTI, AFM is an invasive imaging technique that requires the extraction of the tissue to be tested. Shear elasticity is evaluated using Van der Waals interactions forces between the cantilever tip and the tissue, resulting in the deviation of a laser light pointing to the cantilever. Thanks to the laser light reflection, the machinery is able to quantify the height of the cantilever, obtaining the sample rigidity [33, 34]. Similarly, indentation is an invasive procedure consisting in the measurement of the machine tip penetration area on the sample surface. Qian et al. [35] raised some questions about the homogeneity of the results using indentation methods. In case of brain-like soft biomaterials, indentation methods show values with high deviations due to reasons related to structural architecture and heterogeneity of the tissue: (1) the heterogeneity of the biomaterial could lead to difficulties in the test operation. Indeed, a non-flat tissue, which presents numerous asperities (e.g. the brain), shows inaccurate values; (2) in some tissues, the hypothesis of isotropy used in the analytical models for data analysis could be not accurate and this may have a repercussion on the quality of the experiments outputs; (3) a universal protocol for indentation techniques is lacking, allowing user-related variation of the boundary conditions in the experimental setup; (4) the brain stiffness changes according to the tested regions [36]. In vitro AFM and indentation present a technical limitation regarding the small size of the samples that could lead to an erroneous global stiffness measurement [34]. Moreover, it is relevant to highlight that ECM stiffness increase data were obtained only in experiments performed on mice brain samples. This aspect combined with additional data obtained from mouse and bovine models supported the ECM stiffness decrease with aging, showing a direct correlation between myelin concentration and cerebral elasticity [37, 38]. In particular, Weickenmeier et al. [38] found that in bovine brain white matter an increased percentage of myelin leads to a more stiffen tissue. Indeed, a myelin content of 63% showed a stiffness of 0.5 kPa, while a myelin content of 92% matched with a stiffness of 2.5 kPa (Fig. 3). The same Authors confirmed the correlation between myelin content and stiffness in a following study on human brain [39]. Since it has been reported a reduction in the myelin amount during aging [40, 41], it is reasonable to suppose that stiffness decreases with aging. In literature, there is a consensus about the decrement of AD patients’ ECM stiffness compared with the age-matched healthy patients (Table 2). Further experiments on this topic have been conducted on both mice and human brain tissue using different techniques. MRE and multifrequency magnetic resonance elastography (MMRE) have been performed on living subjects [42,43,44,45,46,47,48], while nanoindentation and AFM have been executed in vitro [49, 50]. As an example of stiffness value, in post-mortem human brain tissue has been reported a decrement in stiffness of ∼23.5% for grey matter and ∼27.9% for white matter [49]. These data suggest that ECM stiffness is region-dependent, as this has been further confirmed by experiments on mice brain and on post-mortem human brain samples [36, 51]. Results obtained using in vitro techniques (i.e. nanoindentation and AFM) on the AD hippocampal region were in accordance with the data obtained with non-invasive procedures (i.e. MRE and MMRE). As already discussed, stiffness decrease may be caused by myelin loss occurring both in aging and in AD progression [37, 38, 40, 41, 50]. In line with this, experimental observations in AD exhibited further myelin loss compared to physiological aging [40, 50].

Correlation of myelin percentages with the stiffness of the white matter of a bovine brain. The plot shows the correlation of white matter stiffness in a bovine brain with myelin percentage of the tissue [38]

The nuclear lamina is a nuclear structure that represents the final component of the force transmission pathway from the extracellular matrix to the nucleus. Indeed, the nuclear lamina consists of a nuclear structure that is sensitive to extracellular matrix changes, provides support and a stress-related shield for the inner nuclear membrane. It is a meshwork composed by four intermediate filament proteins (A, B1, B2, C). Nuclear lamina is localized in the proximity of the nuclear inner membrane and it is connected to peripheral chromatin [52]. It is involved in several cell mechanisms and functions such as DNA replication, nuclear and chromatin organization, cell development and differentiation [52]. In physiological conditions, lamin A/C is highly expressed in stiff tissues, whereas it is almost absent in soft tissues such as the brain [53]. Lamin A/C enrichment, which leads to higher nuclear stiffness, may act as a genome protective agent [53, 54]. As for lamin B1, it is necessary for the nuclear shape maintenance, while lamin B2 is important for the neuronal migration during development [55, 56]. In physiological conditions, nuclear lamina is highly dynamic and sensitive to extracellular matrix variations through the mechanotransduction pathways. Indeed, like the ECM, the nuclear lamina showed significant alterations in terms of quantity and thickness during AD progression. In fact, in AD lamin A/C levels increased causing the nuclear envelope stiffening and altering the spatial arrangement of the nuclear scaffold [57, 58]. On the other hand, the lamin B1 reduction leads to a functional and morphological cell nucleus alteration [4, 57, 59]. These data were collected using ex-vivo mice or human brain samples by different techniques, such as immunohistochemistry, immunofluorescence microscopy and Western blotting (Table 3). These immunological techniques are able to evaluate the level of lamin A, lamin B1 and lamin B2 [60,61,62]. It was found that the levels of lamin A and B2 in neurons of AD subjects increased [