The idea that alterations in the brain immunomodulation are critical for Alzheimer's disease (AD) pathogenesis provides the most integrative view on this cognitive disorder, considering that converging research lines have revealed the involvement of inflammatory processes in AD. We have proposed the damage signal hypothesis as a unifying scheme in that release of endogenous damage/alarm signals, in response to accumulated cell distress (dyslipidemia, vascular insults, head injury, oxidative stress, iron overload, folate deficiency), is the earliest triggering event in AD, leading to activation of innate immunity and the inflammatory cascade. Inflammatory cytokines play a dual role, either promoting neurodegeneration or neuroprotection. This equilibrium is shifted toward the neurodegenerative phenotype upon the action of several risk factors that trigger innate damage signals that activate microglia and the release of tumor necrosis factor-alpha, interleukin-6, and some trophic factors. In this neuroimmunomodulatory hypothesis we integrate different risk factors with microaglial activation and the resulting neuronal alterations and hyperphosphorylations of tau protein. The progression of AD, with slowly increasing damage in brain parenchyma preceding the onset of symptoms, suggests that tissue distress triggering damage signals drives neuroinflammation. These signals via toll-like receptors, receptors for highly glycosylated end products, or other glial receptors activate sensors of the native immune system, inducing the anomalous release of cytokines and promoting the neurodegenerative cascade, a hallmark of brain damage that correlates with cognitive decline.

Lifestyle factors such as intellectual stimulation, cognitive and social engagement, nutrition, and various types of exercise appear to reduce the risk for common age-associated disorders such as Alzheimer’s disease (AD) and vascular dementia. In fact, many studies have suggested that promoting physical activity can have a protective effect against cognitive deterioration later in life. Slowing or a deterioration of walking speed is associated with a poor performance in tests assessing psychomotor speed and verbal fluency in elderly individuals. Fitness training influences a wide range of cognitive processes, and the largest positive impact observed is for executive (a.k.a. frontal lobe) functions. Studies show that exercise improves additional cognitive functions such as tasks mediated by the hippocampus, and result in major changes in plasticity in the hippocampus. Interestingly, this exercise-induced plasticity is also pronounced in APOE ε4 carriers who express a risk factor for late-onset AD that may modulate the effect of treatments. Based on AD staging by Braak and Braak (1991) and Braak et al. (1993) we propose that the effects of exercise occur in two temporo-spatial continua of events. The “inward” continuum from isocortex (neocortex) to entorhinal cortex/hippocampus for amyloidosis and a reciprocal “outward” continuum for neurofibrillary alterations. The exercise-induced hypertrophy of the hippocampus at the core of these continua is evaluated in terms of potential for prevention to stave off neuronal degeneration. Exercise-induced production of growth factors such as the brain-derived neurotrophic factor (BDNF) has been shown to enhance neurogenesis and to play a key role in positive cognitive effects. Insulin-like growth factor (IGF-1) may mediate the exercise-induced response to exercise on BDNF, neurogenesis, and cognitive performance. It is also postulated to regulate brain amyloid β (Aβ) levels by increased clearance via the choroid plexus. Growth factors, specifically fibroblast growth factor and IGF-1 receptors and/or their downstream signaling pathways may interact with the Klotho gene which functions as an aging suppressor gene. Neurons may not be the only cells affected by exercise. Glia (astrocytes and microglia), neurovascular units and the Fourth Element may also be affected in a differential fashion by the AD process. Analyses of these factors, as suggested by the multi-dimensional matrix approach, are needed to improve our understanding of this complex multi-factorial process, which is increasingly relevant to conquering the escalating and intersecting world-wide epidemics of dementia, diabetes, and sarcopenia that threaten the global healthcare system. Physical activity and interventions aimed at enhancing and/or mimicking the effects of exercise are likely to play a significant role in mitigating these epidemics, together with the embryonic efforts to develop cognitive rehabilitation for neurodegenerative disorders.

bvFTD selectively affects Network Centrality in the frontotemporoinsular network, which is associated with high-level social and executive profile.

Substance P (SP)-, leucine-enkephalin (LENK)-, cholecystokinin octapeptide (CCK8)-, bombesin (BOM)-, and avian pancreatic polypeptide (APP)-like immunoreactivities were analyzed in the optic tectum of Rana pipiens 5-99 days after unilateral eye enucleation, or optic nerve ligation, by means of the peroxidase-antiperoxidase and indirect fluorescence single and double labeling methods. The normal pattern (Kuljis and Karten, '81, '82c) of peptide-like immunoreactivity was observed ipsilaterally to the operation. Contralateral deafferented tectae displayed conspicuous modifications in the normal pattern of peptide-like immunoreactivity unique to each of the substances studied. The modifications of peptide-like immunoreactivity observed varied depending both on the survival time and on the particular peptide analyzed, with either increment or diminution or disappearance--or combinations thereof--in the staining intensity of some of the peptide-positive bands in the superficial one-third (superficial neuropil) of the tectum. The onset of these changes is detectable immunocytochemically between the sixth and tenth day following deafferentation. By 2-4 weeks full expression of the long-term changes is reached with no apparent further modification up to the 99th postoperative day. The rapid onset of these phenomena suggests the existence of a previously unrecognized retinal ganglion cell terminal peptidergic contribution to the tectum and/or rapid transsynaptic effects. The former possibility is suggested by recent observations demonstrating peptide-like immunoreactivity for SP, LENK, CCK8 and BOM in the retinal stump of ligated optic nerves (Kuljis and Karten, '82b). The fact that no vertebrate retinal ganglion cells have been shown to contain any of these peptides (Brecha et al., '79; Famiglietti et al., '80; Eldred and Karten, '81; Karten et al., '82), however, argues against the possibility of a retinal terminal contribution to peptide-like immunoreactivity in the tectum and suggests that transsynaptic phenomena are involved.

Virtually none of the hypotheses on Alzheimer's disease (AD) pathogenesis address the earliest events that trigger the molecular alterations that precede cerebral degeneration and account for the diversity of risk factors that converge on a well-defined disease phenotype. We propose that long-term activation of the innate immune system by an individual array of risk factors constitutes a unifying mechanism leading to the triggering of an inflammatory cascade that converges in cytoskeletal alterations (tau aggregation, paired helical filament formation) as a previously hypothesized final common pathway in AD. The key pathogenic phenomena consist in the long-term, maladaptive activation of innate immunity-triggering receptors -such as the toll-like and advanced glycation end-products receptors, and others located in the microglial membrane -by seemingly heterogeneous risk factors such as hyperlipidemia, hyperglycemia, oxidative stress, head injury, amyloid oligomers, etc. Our hypothesis provides a unifying mechanism that explains both the diversity of risk factors acting over long periods of time and the individual response to such insults. This formulation is amenable to both empirical testing and implementation into therapeutic strategies that may lead to effective prevention of AD as well as other disorders in which impaired regulation of the innate immunity is the unifying cause of the condition.

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Neural degeneration is one of the clinical manifestations of ataxia-telangiectasia, a disorder caused by mutations in the Atm protein kinase gene. However, neural degeneration was not detected with general purpose light microscopic methods in previous studies using several different lines of mice with disrupted Atm genes. Here, we show electron microscopic evidence of degeneration of several different types of neurons in the cerebellar cortex of 2-month-old Atm knockout mice, which is accompanied by glial activation, deterioration of neuropil structure, and both pre-and postsynaptic degeneration. These findings are similar to those in patients with ataxia-telangiectasia, indicating that Atm knockout mice are a useful model to elucidate the mechanisms underlying neurodegeneration in this condition and to develop and test strategies to palliate and prevent the disease.

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