Potential of molecular chaperones for treating Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent form of dementia, i.e., progressive memory loss and profound cognitive dysfunction, resulting in a considerable societal burden. At the neuropathological level, the brains of AD patients exhibit amyloid-β (Aβ) plaques, neurofibrillary tangles, and neuroinflammation (Sala Frigerio and De Strooper, 2016). The growing number of individuals affected with AD underscores the pressing need for the development of effective treatments, and a cure remains elusive. The pathogenesis of AD involves intricate molecular and cellular mechanisms that lead to progressive neurodegeneration and cognitive decline. A central tenet of AD pathogenesis is the amyloid cascade hypothesis, which posits that the accumulation of Aβ peptides plays a pivotal role in disease progression. Aβ derives from the amyloid precursor protein (APP) by BACE1 (β-secretase) and γ-secretase cleavages, and aggregates into plaques that eventually disrupt neuronal function. Concurrently, abnormal phosphorylation of the tau protein leads to the formation of neurofibrillary tangles, contributing to neuronal degeneration. Neuroinflammation, oxidative stress, mitochondrial dysfunction(definition), and synaptic impairment further compound the pathology (Sala Frigerio and De Strooper, 2016). The intricate interplay of these phenomena underscores the challenges in treating AD, necessitating innovative therapeutic approaches to halt or slow disease progression effectively. Recently, monoclonal antibody drugs, like Aducanumab, Lecanemab, and Donanemab, have shown the ability to decelerate memory and cognitive decline in phase III clinical trials of early-stage AD (Boxer and Sperling, 2023). Aducanumab is designed to bind Aβ aggregates in both the oligomeric and fibrillar states rather than amyloid monomers, while Lecanemab has been proposed to target so called Aβ protofibrils. Donanemab is directed against N-terminally modified form of Aβ. These clinical trials collectively suggest that the approach to target Aβ represents an effective strategy for treating AD, particularly in its early stages. While antibody drugs have gained significant attention for their effects in mitigating memory and cognitive deterioration in early-stage AD, several crucial aspects warrant consideration, including (1) Efficacy and side effects: While the antibodies do play a role in slowing the progression of AD, the magnitude of their efficacy may vary, and the benefits need to be weighed against the probability of side effects (Boxer and Sperling, 2023). This underscores the importance of a thorough assessment of both the benefits and potential drawbacks of these drugs. (2) Blood-brain barrier permeability: The development of compounds for AD faces a notable failure rate, with many tested compounds, particularly antibodies, exhibiting poor permeability across the blood-brain barrier. This limitation poses an obstacle in treating central nervous system disorders and emphasizes the need for innovative approaches to enhance drug delivery. (3) Late-stage AD treatment: AD is typically diagnosed in its later stages, characterized by observable cognitive decline and memory impairment. It remains unclear whether drugs effective in early-stage AD exhibit the same efficacy in later stages. This highlights the necessity for treatment strategies that take into account the evolving nature of the disease. (4) Multifactorial nature of AD: Aβ is recognized as a significant contributor to AD, but it is probably not the sole driving force, and factors like tau pathology, neuro-inflammation, and oxidative stress also play integral roles. Thus, there is a growing acknowledgment of the need to develop interventions that comprehensively target the multifactorial aspects of AD. Molecular chaperones play a crucial role in preserving cellular protein homeostasis (proteostasis(definition)). ATP-independent molecular chaperones, often referred to as “holdases”, maintain (partially) unfolded client proteins in a folding-competent state without necessarily refolding them, leaving the task of refolding or degradation to other cellular systems. Experimental data suggest that these chaperones, including small heat shock proteins (sHsps), can prevent or resolve protein aggregation also in neurodegenerative diseases including AD. For instance, Hsp27 (HspB1) impedes the formation of tau fibrils by engaging in weak interactions with early species during the aggregation process, and mitigates the toxicity of Aβ oligomers by sequestering them and transforming them into larger, non-toxic aggregates (Wentink et al., 2019). αB-crystallin (HspB5) binds to both wildtype Aβ42 fibrils and fibrils formed from the Aβ42E22G (Arctic) mutant and subsequently inhibits amyloid fibril formation (Wentink et al., 2019). Further, Nuclebindin-1 (NUCB1), identified as a novel chaperone-like amyloid-binding protein, demonstrates inhibitory effects on the aggregation of islet amyloid polypeptide (IAPP) linked to type 2 diabetes, α-synuclein associated with Parkinson’s disease, transthyretin V30M mutant related to familial amyloid polyneuropathy, and Aβ42 (Bonito-Oliva et al., 2017). In contrast, ATP-dependent molecular chaperones assist substrates in adopting their native conformation (“foldases”) or prepare them for degradation. DNAJB6, a member of the Hsp40 heat shock protein family, demonstrates a high efficiency in inhibiting Aβ42 amyloid formation (Wentink et al., 2019). The extracellular secretion of Hsp70 demonstrates protection against Aβ42-induced toxicity, effectively mitigating neurotoxicity in adult eyes, reducing cell death, preserving the structural integrity of adult neurons, alleviating locomotor dysfunction, and extending lifespan. Additionally, engineered Hsp70 chaperones prove effective in preventing Aβ42-induced memory impairments in a Drosophila model (Wentink et al., 2019). While the majority of information about molecular chaperones centers around sHSPs primarily located intracellul