The AD Brain
The Alzheimer's disease brain. What makes it different from the normal brain and why does it strip someone of their memory, thinking abilities, and personality?
The brain is composed of cells which help provide structure and maintain function to this essential organ. The two main types of cells in the brain are neurons and glia. There are lots of other cells in the brain - so just be aware of that, but these are the main players - at least that's what current neuroscience tells us. I like to think of neurons as providing the main highways for thought and memory to occur; and glia as the maintenance crews that provide insulation, clean up, and help keep traffic moving in the brain. It has been estimated that there are over 100 billion neurons in the human brain. Yes, 100 billion. Imagine that all of these neurons are interconnected by one of the most complex highway systems you could ever imagine. Rewind back to high school biology and you'll probably recall a picture of gangly looking blobby star with a long tail protruding on one side. Ahhh yes - the neuron and its axon. Neurons can come in all shapes and sizes, depending on where they're located in the brain and what their main input and output will be. For simplicity's sake, let's just say that there's: 1) the cell body (or if you want to sound fancy - the soma) of the neuron, where the nucleus (the control center), mitochondria (the power plant), and other important cellular components reside, 2) dendrites which project from the soma (basically making the ends of the star-like shape) and 3) the axon, which is composed of long tube-like structure (a microtubule if you want to get technical) to help transmit molecules and signals down the cell. These signals are basically messages sent from one neuron to another (via dendrites and axons) and ultimately give rise to our thought, memory and action. As many of you probably know neurons communicate with one another via synapses, which is where the axon terminal (or end of the axon) of one neurons contacts another neuron (at either a dendrite, soma or axon). This communication, also called synaptic transmission, is triggered by an action potential, depolarizing the neuron's membrane and releasing neurotransmitters to further propagate the signal to the next cell. Disruptions in this process can lead to deficits in learning and memory.
The Alzheimer's brain
Borrowing John Hardy's analogy (he helped discover the early-onset Alzheimer's disease genes and the amyloid hypothesis), imagine you just walked into a stadium after a game. There's popcorn strewn around, foam fingers, empty cups, maybe some confetti and a toppled-over Gatorade jug. Now...based on the state of the arena...try to guess who won the game. That's basically what it's like for an Alzheimer's researcher. We try to recapitulate the disease, but that's all we can do...we can't open up a person's brain and see how its caused and progressing throughout the disease. We only get a glimpse of the Alzheimer's brain after the fact, after the game has occurred...and then must try to deduce how it happened.
As you probably know, the main features of the Alzheimer's brain are plaques and tangles. Other important features include: the loss of brain cells (or neurons), the loss of synapses, the activation of glial cells (microglia and astrocytes), and increased inflammation. In early-onset AD we know that mutations in amyloid precursor protein (APP), presenilin 1, or presenilin 2 lead to increased amounts of β-amyloid (or abbreviated Aβ), which is ultimately accumulated in the brain in the form of amyloid plaques. I like to think of plaques as garbage dumps in the brain. Normally, cells (either microglia or neurons) in the brain can degrade or get rid of toxic proteins, debris, or other unwanted material, but due to either the overwhelming production or inefficient clearance of Aβ, they can't. Recent studies point to the small Aβ protein forms (oligomers) as the more toxic species (and thus brain cell death-promoting agents). I believe that plaque formation is a way for the brain to corral all the toxic proteins into one place...where it can do less damage vs. cause more dispersed damage throughout the brain. Researchers predict that Alzheimer's proceeds accordingly: gradual deposition of toxic Aβ, problems in synaptic function, formation of plaques, activation of glia cells (and their associated increased inflammatory responses), altered ion homeostasis (i.e. altering cellular membrane dynamics and potential), oxidative stress and injury, accumulation of phosphorylated tau (via altered kinase/phosphatase activity) and neurofibrillary tangles, widespread neuronal and synaptic dysfunction and loss, alterations in neurotransmitters, and finally dementia.
In support of this, a recent study showed that individuals with a mutation in APP, which in this case leads to a decrease in Aβ, helps protect individuals from developing Alzheimer's. However, to focus on Aβ would negate findings that show no correlation between amyloid deposition in the brain and cognitive decline. In fact, tau and tangle accumulation correlates with cognitive decline. Thus, it is clear that both of these pathologies are necessary for Alzheimer's disease to occur, however, it remains unclear how these two are linked mechanistically in the causality of Alzheimer's disease and, most important, how we can best target them for disease prevention or delay.
Structural features and potential biomarkers of the Alzheimer's brain.
Structural imaging of the AD brain reveals gross atrophy of the cerebral cortex and dilation of the lateral ventricles during disease progression (Banich, 2004; McKhann et al., 2011). However, these features are also common in the normal aging brain. More recently, studies have identified medial temporal lobe atrophy (entorhinal cortex and hippocampus atrophy) as a prominent feature of the AD brain that correlates well with dementia and clinical status (Johnson, Fox, Sperling, & Klunk, 2012). Other AD features or biomarkers include positive amyloid positron emission tomography (PET) imaging, reduced 18fluorodeoxyglucose (FDG) metabolism in the temporoparietal cortex, decreased cerebrospinal fluid (CSF) levels of β-amyloid42 (Aβ42), and elevated CSF levels of total tau (t-tau) and phosphorylated tau (p-tau) (Johnson et al., 2012; McKhann et al., 2011). These advances in neuroimaging techniques and CSF biomarkers play an important role in differentiating AD from other dementias with overlapping symptoms and pathologies; however, current diagnostic tools still lack a specific physiological test to make a definitive AD diagnosis (Banich, 2004). As such, an irrefutable diagnosis of AD can only be made once a post mortem examination has confirmed the presence of classical AD histopathological lesions.
The pathological features of the Alzheimer's brain.
The deposition of extracellular senile plaques and intracellular neurofibrillary tangles are considered the cardinal pathological hallmarks of AD. Other features include the loss of neurons and synapses, the loss of white matter, congophilic/cerebral amyloid angiopathy (CAA), inflammation, oxidative stress, cerebrovascular dysfunction and cholinergic neurodegeneration in the basal forebrain (Braak & Braak, 1991; Mufson, Counts, Perez, & Ginsberg, 2008; Perl, 2010; Querfurth & LaFerla, 2010; Serrano-Pozo, Frosch, Masliah, & Hyman, 2011).
Tau and neurofibrillary tangles. Neurofibrillary tangles are primarily composed of abnormally hyperphosphorylated aggregates of the microtubule-associated protein tau. Tau is normally located in axons, where it facilitates axonal transport and promotes the assembly and stability of microtubules. In neurodegenerative diseases, tau phosphorylation (normally regulated by tau kinases and phosphatases) becomes dysfunctional leading to its abnormal hyperphosphorylation and aggregation into tangle-forming fibrils. In AD, tau undergoes abnormal phosphorylation, misfolding, and aggregation, ultimately leading to the formation of neurofibrillary tangles. Although these tangles are also present in other neurodegenerative diseases, the progressive deposition and distribution of these tangles correlates well to the severity and duration of AD-associated cognitive decline (Querfurth & LaFerla, 2010). This progressive tangle spreading has been shown to propagate in a predictable pattern. First, tangles accumulate in the medial temporal lobe or specifically in the entorhinal cortex, where they then progress to the limbic and association cortices (de Calignon et al., 2012). The motor, sensory, and visual isocortical areas are spared until the later stages of disease (Perl, 2010; Serrano-Pozo et al., 2011).
β-amyloid and senile plaques. Senile plaques are primarily composed of β-amyloid (Aβ) peptides, byproducts of amyloid precursor protein (APP) metabolism following its sequential cleavage by the enzymes β- and γ-secretase. This cleavage of APP results in the generation of two Aβ species: Aβ40 and Aβ42 (LaFerla, Green, & Oddo, 2007). The proteolytic processing of amyloid precursor protein (APP) by β-secretase and subsequently γ-secretase gives rise to the production of Aβ fragments, which accumulate and aggregate to form oligomers and plaques. Many of the mutations associated with FAD influence β- or γ- secretase to promote the amyloidogenic pathway (production of plaque-forming Aβ) of APP metabolism. The cleavage of APP can also occur through an alternative pathway that involves alpha-secretase, which results in the release of non-amyloidogenic (non-plaque forming) fragments. Aβ40 is the more prevalent isoform found in vivo and serves as a major component of CAA—Congo Red-positive Aβ deposition in cerebral blood vessels (LaFerla et al., 2007; Serrano-Pozo et al., 2011). Aβ42 makes up only 10% of the total secreted Aβ, but is the more predominant species found in plaques due to its enhanced hydrophobicity, aggregation and fibrillization potential. It can spontaneously self-aggregate to generate soluble neurotoxic oligomers or insoluble fibrils that go on to form plaques (LaFerla et al., 2007; Querfurth & LaFerla, 2010). Similar to tangle pathology, amyloid plaques also progress in the brain following a certain distribution pattern, but unlike tangles typically originate and spread from the isocortex.
Although plaques are a common characteristic of the AD brain, plaques are also visible in brains of healthy elderly individuals. However, studies have shown that there is a clear distinction between amyloid plaques laden in the brains of AD patients (compact/dense-core plaques) and those found in non-demented elderly individuals (diffuse plaques). Diffuse plaques contain amorphous non-aggregated Aβ (Thioflavin S- and Congo Red-negative), whereas dense-core plaques contain Aβ fibrils arranged radially into a central core. More importantly, these plaques are typically surrounded by dystrophic neurites, reactive astrocytes, activated microglial cells, and synaptic loss. Abnormal mitochondria and lysosomes have also been found within these activated cells, indicating that energy or protein degradation processes may be compromised. Many researchers claim that these neuritic plaques represent the most visible evidence for Aβ’s involvement in AD pathogenesis (Perl, 2010; Serrano-Pozo et al., 2011). However, the more convincing evidence for this hypothesis has come from familial AD genetic analysis.
Genetically, AD is classified into two forms: early-onset or familial AD (FAD) and “sporadic” or late-onset (patients over 60-65 years of age) AD. Genetic analysis using family linkage studies and DNA sequencing has identified three genetic loci that cause AD in early-onset FAD mutation carriers (Bertram, Lill, & Tanzi, 2010; Tanzi, 2012). These mutations are mostly inherited in an autosomal-dominant manner and are found in genes that encode the proteins APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2). No mutations have been found in the gene encoding tau in AD patients (Gotz & Ittner, 2008). Missense mutations in APP have been shown to influence the proteolytic processing of APP and the subsequent aggregation of Aβ. Mutations in PSEN alter γ-secretase-mediated proteolytic cleavage of APP ultimately leading to an increase in the ratio of Aβ42: Aβ40 levels (Mayeux & Stern, 2012). This increase in Aβ, by abnormal Aβ production or aggregation or by reduced Aβ clearance, promotes its aggregation into oligomers and subsequently plaque-forming fibrils (Tanzi, 2012). Although FAD represents a small proportion (< 1-5 %) of all AD cases, the discovery of these disease-causing mutations and their associated phenotype has played a pivotal role in identifying the mechanisms that lead to AD pathogenesis (Gotz & Ittner, 2008; LaFerla & Green, 2012; Tanzi, 2012). This includes providing evidence for the “amyloid hypothesis,” which postulates that Aβ plays a causal role in triggering the events leading to AD (Bertram et al., 2010; Hardy & Selkoe, 2002).
The important questions (that I think) that still remain: What is the normal function of Aβ? How does increased amyloid and tangle deposition in the brain lead to memory loss? What is the best way to prevent neurodegeneration and memory loss? Is it targeting and getting rid of amyloid, tau, or something else? Why do some people with early-onset Alzheimer's (despite having the same mutation) develop age of onset earlier or later? What happens when someone "escapes" age of onset despite testing positive for the mutation? Can we target this for others therapeutically?