Novel Development and Prospects in Pathogenesis,Diagnosis,and Therapy of Alzheimer’s Disease

Amyloid-cascade hypothesis

In the pathogenic phase of AD, amyloid-β (Aβ) accumulation and abnormally hyperphosphorylated tau protein are the primary regulatory factors. The development of amyloid plaques was caused by extracellular Aβ accumulation [10], and neurofibrillary tangles were brought on by intracellular tau phosphorylation [11]. And the development of neurofibrillary tangles and amyloid plaques induced the further synapse loss and cognitive dysfunction. In line with the amyloid-cascade theory of Aβ production [12], sAβPPβ, Aβ, and the intracellular domain of AβPP (AICD) were released from AβPP by β-secretase and γ-secretase cleavage, respectively (Fig. 1). γ-secretase [13] consisting of nicastrin, PSEN 1, PEN 2 (presenilin enhancer 2) and APH 1 (anterior pharynx defective 1) as the essential components plays the crucial role in above process.

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Fig. 1

In line with the amyloid-cascade theory of Aβ production, sAβPPβ, Aβ peptides, and the intracellular domain of AβPP (AICD) were released from AβPP by β-secretase and γ-secretase cleavage, respectively. The essential components of γ-secretase include nicastrin, PSEN 1, PEN 2 and APH 1. In the non-amyloidogenic pathway, sAβPPα, P3 peptides, and AICD were produced by α-secretase and γ-secretase cleavage, respectively.

According to the recent finding on clinical drug trials for AD, γ-secretase enzyme may be a promising therapeutic target for controlling Aβ level regulation [14]. Therefore, specific γ-secretase inhibitors, modulators that particularly reduce of Aβ₄₂ production, or stabilizers that produce longer Aβ peptides (≥42) [15], in combination with other therapies that target hyperphosphorylated tau or neuroinflammation, may be used to effectively slow down the pathological progression and development of AD from early to later stages. Such Aβ production, which largely includes Aβ_1–40 and Aβ_1–42 in above pathological process of amyloidogenic pathway played the major role in the development of the pathological process of AD [16]. Aβ_42/40 is currently a critical biomarker of AD clinical diagnosis by positron emission tomography (PET)-computed tomography (CT) or cerebrospinal fluid (CSF) checking [17]. Additionally, mutations in the genes for A βPP, PSEN1, and PSEN2 could lead to or accelerate the accumulation of Aβ peptides [18], and these alterations were the specific genetic background on fAD etiology.

More studies have recently offered various newly proofs that intracellular Aβ (iAβ) [19], a biomarker or intracellular modulator, may have a great impact on the pathological progression of AD. The production of iAβ, the import of extracellular Aβ, and the clearance of iAβ [20], however, would help to clarify the mechanism of iAβ accumulation and provide more information on the effects of Aβ toxicity on synapse dysfunction. Our latest study [21] also evidenced that γ-secretase inhibitor regulated iAβ toxicity by slowing down endocytosis, which was associated to N-cadherin-CTF, a synaptic cell adhesion molecule. These recent findings may offer novel insight into the molecular mechanism of AD and provide new prospective targets for drug discovery and development. The regulation of synaptic morphology and plasticity was associated with the AβPP [22], which functions as a synaptic adhesion molecule. Other synaptic adhesion molecules, such as cadherin [23], neurexin, neuroligin [24], LRRTM3 [25], and NCAM [26], also have significant effects on AD’s pathophysiology. Additionally, a plausible cause of synapse loss or dysfunction could be an interaction between the synaptic adhesion molecules and Aβ toxicity on the synapses.

These Aβ effects were the main cause of neurodegeneration in familial AD, and Aβ accumulation and aggregation may be responsible for the pathogenic changes in hyperphosphorylated tau protein. Thus, synergistic effect of Aβ and tau should be taken into consideration.

Synergistic effect of Aβ and tau

Aβ and tau play the crucial roles in the pathological progression of AD and are, in theory, the most significant therapeutic targets for ongoing new medication research in this area. Many options for anti-Aβ deposition and anti-tau protein hyperphosphorylation were able to exhibit good pharmacological effects in pre-clinical investigations [27, 28] in accordance with the needs of drug design by reducing Aβ protein deposition or lowering tau protein hyperphosphorylation, respectively. It would also be in keeping with the original purpose of anti-AD drug creation and might dramatically slow the trajectory of cognitive loss in AD animal models [29]. Although the above-mentioned candidate drugs could still limit the level of tau protein hyperphosphorylation and reduce Aβ deposition in the brains of AD patients. Most clinical trials to far have failed because additional clinical investigations [30, 31] have demonstrated that the decline in cognitive function of these patients has not been significantly reversed or modified.

PET molecular neuroimaging was able to detect both total or hyperphosphorylated tau and Aβ distribution in the brain, it has been proved that the pathological changes of tau protein were independent with Aβ accumulation [32], both tau and Aβ might be occurred in distinct “time windows” of AD development. Additionally, neuroimaging data also demonstrated [33] that such changes to Aβ and tau were seen in several targeted regions during the early stages of AD, with tau showing up earlier among these changes. In the early stages of AD, hyperphosphorylated tau is dispersed alone in the entorhinal cortex of the brain without the presence of Aβ [34]. Such hyperphosphorylated tau detected solely by PET in the particular neurofibrillary tangles in the absence of Aβ accumulation provided the additional proof that the pathological process of tau protein may be the alternative pathway independent of Aβ in the development of AD pathology. Furthermore, it is evident that Aβ accumulation in the late stages of AD could facilitate or enhance tau distribution in the neocortex, promoting AD-related neurodegeneration [35].

As a result, this concept offers the novel insights into the pathological process of sporadic AD, and studying the synergistic interaction between Aβ and tau will help us clarify more details of the mechanism of AD. Furthermore, tau-mediated neurodegeneration, which is independent with the Aβ pathway, has an additional impact on the pathological process of AD [33], which may be part of the reason why anti-Aβ therapies applied solely by only removing Aβ obviously from clinical AD patients were unable to improve or reverse the cognitive decline. In addition, Phosphokinases CDK 5 [36], GSK 3[37], and ERK2 [38], may also control tau protein hyperphosphorylation in sporadic AD.

Even though it has been established that the pathological changes of tau protein were independent of the accumulation of Aβ, the relationship between the two remains controversial. Since the molecular mechanism underlying AD pathogenesis is still unclear, more experimental data and research will be required to investigate it in the years to come. These additional investigations will support a theoretical framework for clarifying the pathological mechanisms and signaling pathways associated with AD, as well as present new pharmacological targets and therapeutic approaches for the clinical treatment of AD patients. Due to the synergistic effects of Aβ and tau discussed above, a combined therapeutic strategy using anti-tau and anti-Aβ may have an anticipated positive impact on the future clinical care of AD patients.

Neuroinflammation

In addition to the amyloid cascade hypothesis of AD, neuroinflammation brought on by activated microglia was found to be one risk factor contributing to changes in Aβ and tau pathology [39, 40]. Pathological tau protein can induce the production of IL-1 via exacerbating neuroinflammatory reactions. In hippocampus, tau phosphorylation is decreased by inhibiting adenosine A2A receptors [41]. In the rTg4510 model, LPS may lead to the form of neurofibrillary tangles and hyperphosphorylation of tau [42]. Numerous research on the biomarkers for neuroinflammation have shown that the activation of microglia in such an inflammatory response within the brain led to the release or production of cytokines or chemokines such as IL-3, IL-12, or IL-10, etc. In animal models, stimulation of astrocytes and microglia promotes amyloid accumulation and speeds up inflammatory responses through secretion of cytokines. Research has indicated that there is a greater presence of TNF-α and IL-6 in the brains of individuals suffering from clinical AD. Neurotoxic astrocytes may arise in a neuroinflammatory environment due to the activation of microglia and the release of IL-1, tumor necrosis factor (TNF-α). Furthermore, these neurotoxic astrocytes are unable to support the development of new synapses [43, 44].

Recent clinical studies [45] have demonstrated that AD patients who have higher amounts of IL-12 in their brains, even in the presence of a significant quantity of Aβ accumulation concurrently, will not experience severe cognitive impairment. Intriguingly, tau tangles are rarely seen in the brains of AD patients if IL-12 levels are higher. Additionally, raising the levels of IL-12 and IFN-γ may postpone or slow down cognitive loss, but the precise molecular pathways driving the degenerative course of AD are still unknown. The most recent clinical research report also confirmed that IL-3 released from astrocytes in the brain could control the activation of microglia and reprogram neuroinflammation [46], as well as clear the accumulation of extracellular Aβ plaques and reduce the formation of intracellular tau tangles. However, it is still unknown whether this action of IL-3 could regulate or reverse cognitive decline. This means that the pathogenic changes brought on by these cytokines may dramatically restrict the progression of AD. Furthermore, since the development of synapses is the basis of learning and memory, microglia have the ability to alter or remove existing synapses as well as control synaptic plasticity by remodeling the extracellular matrix. The balance between synapse formation and synapse elimination will be regulated by the effect of neuron-glia communication system [47]. Our latest research [48] shown that hemisynapse formation could be induced on cortical or cerebellar astrocytes following interaction with cortical explant axon by overexpression of the synaptic cell adhesion molecules LRRTM2. This finding may offer a potential approach for treating AD by artificially inducing the newly synapse formation. The process of the neuron-glia communication system also involves the secretion or release of IL-33 and alterations in microglia [49]. Age-related alterations in dendritic spines are all linked to IL-33 and its receptor IL1RL1. The loss of dendritic spines that occurs with aging can be stopped by artificially raising IL-33 levels, which encourages synapses’ remodeling and growth. The aforementioned novel biomarker from blood or CSF may be used in the clinical diagnosis or treatment of AD patients.

According to recent breakthroughs in research on AD therapeutic medications, if anti-Aβ therapy is taken as early as feasible in conjunction with the multi-targeted treatments, it may primarily be successful or delay the onset of clinical symptoms. As a result, early diagnosis using a combination of precise techniques like magnetic resonance imaging (MRI), PET, biomarker measurement, or cognitive score evaluation becomes increasingly crucial and urgent in order to prevent the destructive progression of AD from the early stages to the late phases.

Basic brain imaging

The use of MRI [50], which helps to comprehend and observe the changes in brain structure related to AD pathology, is currently one of the key medical examination techniques used in hospital settings for the diagnosis of AD. A prominent clinical hallmark of dementia brought on by AD is the loss of brain tissue, and an MRI will reveal morphological alterations in AD patients, such as the atrophy of specific brain regions. By assessing the distribution of Aβ or phosphorylated tau in different brain regions from preclinical stage or moderate cognitive impairment to dementia of AD, PET imaging [51] can offer the metabolic changes in AD brain. It’s important to elucidate the pathogenic mechanism of neuroinflammation in animal models and AD patients by using PET molecular imaging. The most neuroinflammatory PET imaging targets is mitochondrial 18 kDa translocator protein (TSPO), and the PET tracer ^[18F]flortaucipir was used to detect tau accumulation and neuroinflammation [52, 53].

Novel CSF or blood biomarkers

Aβ_42/40 is one important biomarker for the diagnosis of AD patient through PET-CT or CSF examination [17]. The clinical diagnostic level of AD will be raised by using single molecule array (SIMOA) or mass spectrometry as high sensitivity immunoassays to measure novel biomarkers in patient plasma or CSF. Therefore, creating simple, timely, affordable, and accurate diagnostic methods based on blood samples can aid us in promptly screening AD patients as early as feasible and in taking early preventative action to slow down the clinical pathological process of AD patients. Neurofilament light [54, 55] has been quantified from patient CSF or plasma samples and utilized as a general indicator of neurodegenerative disease to represent neuronal loss or injury in numerous countries to date. Another novel blood-based AD biomarker is glia fibrillary acid protein [56], which was linked to the pathological alterations on Aβ and released during astrocytic activation. New biomarkers from inexpensive blood tests can change the drawback and limitations on CSF investigation caused by the necessity of lumbar puncture, as well as the existing expensive clinical diagnosis of AD patients using PET imaging. It will aid in the development of novel AD therapeutics. Although the patient does not exhibit any signs of cognitive impairment in the preclinical stage of AD, there are nonetheless neuropathological changes in the tau or Aβ proteins. In the laboratory, it has been reported that several new phosphorylated tau specificities, including p-tau 181, p-tau 217, and p-tau 231 [57–59], have been used by research scientists to assess tau and Aβ pathological process as the novel blood biomarkers for the potential clinical diagnostic method of AD.

Applications of artificial intelligence

Additionally, due to the recent rapid advancement of computational intelligence techniques, computer-aided diagnosis systems for disease using medical artificial intelligence algorithms such as machine learning, deep learning, and convolutional neural network model [60] will provide the most accurate diagnosis and early prevention for AD patients in conjunction with professional physician clinical judgment through the cognitive tests, imaging data, or biomarkers analysis. Using a deep learning algorithm and ¹⁸F-FDG PET imaging [61], it can predict the AD diagnosis. By applying machine learning in conjunction with drawing characteristics and Montreal Cognitive Assessment scores [62], it has been suggested that early identification and diagnosis of cognitive deficiencies will assist enable preventative dementia intervention in clinic. The Digital Neuro Signature from Altoida was used to assess neurocognitive function on an individual basis [63] and was approved as a breakthrough device by the FDA in August 2021. Therefore, in the next years, a basic clinical early evaluation system may screen cognitive capacities of high-risk groups early on by utilizing deep learning and machine learning algorithms in addition to the Mini-Mental State Examination, drawing clock, AD8 test, and other tests. This will play a certain auxiliary role in the early prevention of AD.