Alzheimer’s disease (AD)
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Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia and represents an enormous and growing global public health challenge. It is a uniformly fatal neurodegenerative disorder with no cure or substantially effective treatment. Alzheimer’s Disease International estimated that as of 2013, 44 million people had dementia worldwide, a figure which is expected to increase to 76 million people in 2030 and 136 million in 2050 because of the aging of societies globally (Alzheimer’s Disease International 2013). In the United States, the prevalence of AD in 2015 is estimated at 5 million people, a number which is anticipated to increase to 7 million in 2025 and to 14 million by 2050 (Alzheimer’s Association 2015). AD is a strongly age-associated disorder with onset mainly in later life; the great majority of individuals with the condition are over 65 years of age. Within the older adult population, the prevalence of AD increases dramatically from the sixth through the ninth decade; approximately one-third of individuals with AD currently are 85 years of age or older.

The estimated worldwide cost of dementia was a staggering $604 billion in 2010, with about 70% of the costs being incurred in Western Europe and North America (Alzheimer’s Disease International 2013). In view of the aforementioned epidemiologic trends, massive increases in costs associated with AD are anticipated globally in coming decades if no medical breakthroughs to prevent or cure the disease are developed.

AD is characterized clinically by progressive cognitive impairment, typically beginning as short-term memory impairment, but also notable for executive function deficits, sometimes early behavioral disturbances, and occasionally visuospatial impairment. Over time, the cognitive impairment worsens and affects activities of daily living (ADL). Initially, complex instrumental activities of daily living are impaired, and later, in dementia, basic activities of daily living are lost. The time course is lengthy, with the dementia stage alone often spanning more than a decade. Not only does the disease have a devastating impact on the quality of life for subjects and cause tremendous expense for society, but the protracted course of functional incapacity causes a terrible burden to caregivers, who are also typically elderly, and to other family members and loved ones.

Neuropathologically, Alzheimer’s Disease (AD) is characterized by classic findings of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss, the latter reflected by remarkable macroscopic brain atrophy. Amyloid plaques contain substantial amounts of the amyloid beta (Aβ) peptide, aggregated in dense fibrils, and are surrounded by both dystrophic neurites containing phosphorylated forms of the microtubule associated tau protein and debris thought to be the remnants of dead neurons. Their morphology evolves over time; mature plaques are decorated by activated microglia, and activated astrocytes are also in proximity. The association of astrocytes with plaques appears to precede microglial presence, and the numbers of microglia around advanced plaques appears to be reduced. Neurofibrillary tangles are intracellular structures composed of abnormally and extensively phosphorylated tau protein (p-tau); both plaques and tangles are believed to induce neuronal injury and neuronal death over time. Other important neuropathological features of AD include substantial synaptic loss and a characteristic temporal progression of the distribution of plaques and tangles over the course of the disease.

The correlation between Aβ deposition and the severity of cognitive impairment is relatively weak. Thus, while Aβ may initiate AD and produce some of its pathophysiology, other factors are hypothesized to underlie much of the pathophysiologic progression of the disease. In contrast, tau pathology is strongly associated with cognitive decline in AD. 

Intraneuronal hyperphosphorylated tau is the major constituent of neurofibrillary tangles (NFTs) which represent the hallmark pathological lesion that characterizes several diseases collectively referred to as tauopathies.  In AD, NFTs are accompanied by extracellular plaques containing a different protein, amyloid beta (Aβ).  Neither NFTs or amyloid plaques have been convincingly shown to cause neuronal death, suggesting the existence of other factors, especially soluble neurotoxic substances.  Interaction between Aβ and tau may also be important for disease progression.  An important finding connecting Aβ and tau is the observation that tau is proteolytically cleaved at an aspartate residue (Asp421) in neurons exposed to Aβ (Figure 1).  This cleavage produces the C-terminally truncated tau fragment tauC3. The cleavage occurs by the action of so-called “executioner caspases,” especially caspase-3, which is activated under pro-apoptotic conditions.

Treatment of cortical neurons with fibrillar Aβ induces tau proteolysis at Asp421. From Caspase cleavage of tau:  Linking amyloid and neurofibrillary tangles in Alzheimer’s disease.

Formation of tauC3 also occurs in the AD brain and its level has been correlated with cognitive decline early in the course of the disease (Figure 2).

Figure 2.TauC3 is found predominantly within AD brain and inversely correlated with cognitive function.  From Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.

Importantly, tauC3 exists in lower abundance than FLT or N-terminally truncated tau but exerts disproportionately large pathological effects.  This is due to tauC3 having the highest propensity to aggregate among all forms of tau and its also having the ability to recruit normal tau and nucleate pathological tau conformations.  In recent years, it has been suggested that misfolded or post-translationally modified full length tau can be released from neurons, be internalized by other neurons, and act as a nidus for a new tangle – leading to “propagation” of pathological tau across neuronal pathways. In this regard, it is noteworthy that tauC3 is preferentially secreted by neurons, and as discussed below, also internalized by them.  Moreover, evidence using extracts from human AD brain show that most of all the “seeding” activity is from tauC3.

Neuronal Uptake and Propagation of Tau

It has been suggested that misfolded or post-translationally modified FLT can be released from neurons, be internalized by other neurons, and act as a nidus for a new tangle – leading to “propagation” of pathological tau across neuronal pathways. Such trans-synaptic tau transfer would explain how tau pathology spreads from one region of the brain to another during disease progression. Tau propagation is believed to occur by seed competent aggregated tau i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau. An important clue about the species of tau responsible for tau propagation was the finding that the majority of seeding activity is associated with the high molecular weight (HMW) containing fractions from human AD brain extracts and that this activity is mainly if not entirely associated with truncated tau (Takeda et al., 2015). Further studies conducted by the same group using a highly sensitive FRET-based biosensor cell assay demonstrated that tauC3 represents the active species responsible for a substantial proportion of activity in the AD brain (Figure 3).

Figure 3.Anti-TauC3 antibody recognizes a significant portion of tau seeding activity from human AD lysate in a neuronal aggregation assay. From: Characterization of TauC3 antibody and demonstration of its potential to block tau propagation.